Methods of treatment using bcn057 and bcn512

ABSTRACT

The present disclosure is directed to methods of treating or ameliorating various conditions by the administration of a BCN057, BCN512 or analogs of these compounds. The compounds can be used to reduce tumor burden in cancers, including pancreatic cancer and gastrointestinal (GI) cancer. The compounds can also be used to protect against chemotherapy induced toxicity to the GI tract. Further, they can be used to treat fibrosis and various inflammatory conditions. Analogs of BCN057 and BCN512 are also described.

RELATED APPLICATIONS

This application is a continuation of U.S. patent application Ser. No.17/001,592 which claims priority to U.S. Provisional Patent ApplicationNo. 62/891,338 filed on Aug. 24, 2019. The contents of theaforementioned applications are incorporated herein by reference.

FIELD OF THE INVENTION

The invention relates novel small molecules and their therapeutic use,and more specifically, to therapeutic applications of the smallmolecules BCN057 and BCN512 and analogs thereof.

BACKGROUND

Cancer can be defined as a group of diseases that involve abnormal cellgrowth with the potential to invade or spread to other parts of thebody. Despite advances in technology, cancer continues to be asignificant cause of death and incalculable suffering. Cancer is thesecond most common cause of death in the United States.

Patients with cancer often have limited treatment options. Treatment caninclude a combination of surgery, radiation therapy, chemotherapy andtargeted therapy. Despite advances in research, these treatmentsremained relatively unchanged in recent decades. Efforts have oftenfocused on early diagnosis of cancer when treatments are more effective.However, the survival times afforded by early diagnosis are modest.Recent studies have provided new opportunities for cancer treatment,including the use of Wingless-type (Wnt) pathway modulators.

The Wnt signaling pathways are a group of signal transduction pathwayswhich begin with proteins that pass signals into a cell through cellsurface receptors. Aberrant activation of the Wnt pathway is implicatedin human cancers, particularly those of the gastrointestinal (GI) tract.Inhibition of aberrant Wnt pathway activity in cancer cell lines canblock their growth, presenting the possibility of new therapeutics.Alternatively, activation of Wnt signaling and its downstream genes incancer may induce apoptosis in cancer cells.

The Wnt signaling pathway is often divided into two categories: thecanonical and non-canonical pathways. The canonical pathway is typicallyreferred to as the β-catenin-dependent pathway. The non-canonicalpathway does not rely on β-catenin and is responsible for controllingcell movement during morphogenesis. While both pathways have beenimplicated in cancer development, the canonical pathway is most commonlyrecognized for its implications in gastrointestinal (GI) cancer.

There is a need for improved therapies that can be achieved with Wntsignal modulators. Modulators of Wnt/β-catenin signaling also havepotential in treating other ailments, including fibrosis, inflammatoryconditions, bone growth and alopecia. Accordingly, there is a need forcompounds and methods that can inhibit and/or control Wnt/β-cateninsignaling. Specifically, there is a need for an effective Wnt pathwaymodulator.

SUMMARY OF THE INVENTION

Compound BCN057 disclosed herein were previously described in U.S.patent application Ser. No. 13/813,923 and U.S. patent application Ser.No. 14/889,719. The present invention provides new analogs and newmethods of use. BCN057 (also called YEL002), BCN512 and analogs of eachcompound are described below. The subject compounds are useful for,among other therapies, treating or preventing inflammatory disease andfor treating or preventing cancer or other hyperproliferativeconditions.

One embodiment is a compound of Formula A or an analog thereof,

wherein R₁ is CH₃ or H and R₂ is one of:

Another embodiment is a method of treating an ailment in a subject,comprising administering to the subject a therapeutically effectiveamount of a compound having the structure of Formula B:

wherein:

-   -   R¹ is an alkyl, alkyl amine, or an ether;    -   R² is H or CH₃; and    -   R³ is H or OH.        Analogs of Formula B can include Formula II, Formula III,        Formula IV, Formula V, Formula VI, Formula VII, Formula VIII,        Formula IX, Formula X, Formula XII, Formula XIII, Formula XIV,        Formula XV, Formula XVI, Formula XVII, Formula XVIII and Formula        XIX as described herein.

Additional embodiments include is a method of treating cancer in asubject with a therapeutically effective amount of a compound of FormulaB or an analog thereof. The cancer can be bladder cancer, brain cancer,breast cancer, colorectal cancer, cervical cancer, gastrointestinalcancer, genitourinary cancer, head and neck cancer, lung cancer, ovariancancer, pancreatic cancer, prostate cancer, renal cancer, rectal cancer,skin cancer, blood cancer or testicular cancer. The treatment caninclude administering one or more additional medicaments to the subjectas well as chemotherapy or radiotherapy.

Additional embodiments include a method of treating a subject with oneor more side effects of chemotherapy or radiotherapy with the compoundof Formula B or an analog thereof. Yet another embodiment is a method ofpreventing or treating radiation induced damage to epithelial cells byadministering a therapeutically effective amount of a compound ofFormula B or an analog thereof. The radiation induced damage toepithelial cells can be identified as radiation-induced gastrointestinalsyndrome (RIGS), radiation-induced mucositis, radiation-induced oralmucositis, radiation-induced proctitis and/or radiation-inducedenteritis.

Additional embodiments include a method of treating fibrosis withcompound of Formula B or an analog thereof. The fibrosis can bepulmonary fibrosis, idiopathic pulmonary fibrosis, acute respiratorydistress syndrome, cystic fibrosis, non-cystic fibrosis bronchiectasis,cirrhosis, liver fibrosis, endomyocardial fibrosis, old myocardialinfarction, atrial fibrosis, mediastinal fibrosis, myelofibrosis,retroperitoneal fibrosis, progressive massive fibrosis, nephrogenicsystemic fibrosis, Crohn's disease, gastrointestinal fibrosis, keloidconditions, scleroderma/systemic sclerosis, arthofibrosis, peyronie'sdisease, dupuytren's contracture, oral submucous fibrosis, liverfibrosis, gastrointestinal fibrosis, renal fibrosis from kidney dialysisand/or adhesive capsulitis.

Additional embodiments include a method of treating a viral infection ina subject in need thereof with a compound of Formula B or an analogthereof. Embodiments also include a method of treating depression with acompound of Formula B or an analog thereof.

In one aspect, disclosed herein, is a method of treating a subject witha therapeutically effective amount of the compound BCN057:

BCN057 can also be referred to by its structural name:(3-[(Furan-2-ylmethyl)-amino]-2-(7-methoxy-2-oxo-1,2-dihydro-quinolin-3-yl)-6-methyl-imidazo[1,2-a]pyridin-1-ium).

In another embodiment, the disclosure provides a method of treatingcancer in a subject in need thereof, the method comprising the step ofadministering to the subject a therapeutically effective amount of acompound of BCN057, or an analog thereof. In another embodiment, thedisclosure provides a method of treating cancer in a subject in needthereof, the method comprising the step of administering to the subjecta combination of medicaments that includes a therapeutically effectiveamount of compound BCN057, or an analog thereof.

In another embodiment, the disclosure provides a method of treating sideeffects of chemotherapy or radiation therapy in a subject, the methodcomprising the step of administering to the subject a therapeuticallyeffective amount of a compound of BCN057, or an analog thereof. Inanother embodiment, the disclosure provides a method of treatingradiation-induced gastrointestinal syndrome (RIGS) in a subject, themethod comprising administering to the subject a therapeuticallyeffective amount of compound BCN057, or an analog thereof.

In one aspect, disclosed herein, is a method of treating a subject witha therapeutically effective amount of the compound BCN512. The structureof compound BCN512 is shown below and is also known as1-[(4-nitrobenezene)sulfonyl]-4-phenyl piperazine. Analogs includeBCN512A1 and BCN512B.

In another embodiment, the disclosure provides a method of modulatingWnt signaling in a subject, comprising administering a therapeuticallyeffective amount of a compound of BCN512, or an analog thereof.

In another embodiment, the disclosure provides a method of treating asubject with fibrosis, the method comprising administering to thesubject a combination of medicaments that includes a therapeuticallyeffective amount of a compound of BCN512 or an analog thereof.

In another embodiment, the disclosure provides a method of inhibitingSFRP activity in a subject, the method comprising administering to thesubject a therapeutically effective amount of a compound of BCN512 or ananalog thereof.

In another embodiment, the disclosure provides a method of treatingfibrosis in a subject in need thereof, the method comprisingadministering to the subject a therapeutically effective amount of acompound of BCN512 or an analog thereof. In another embodiment, thefibrotic disease is pulmonary fibrosis, idiopathic pulmonary fibrosis,acute respiratory distress syndrome, cystic fibrosis, non-cysticfibrosis bronchiectasis, cirrhosis, liver fibrosis (caused, for exampleby chronic viral hepatitis B or C), endomyocardial fibrosis, oldmyocardial infarction, atrial fibrosis, mediastinal fibrosis (softtissue of the mediastinum), myelofibrosis (bone marrow), retroperitonealfibrosis, progressive massive fibrosis, nephrogenic systemic fibrosis,Crohn's disease, gastrointestinal fibrosis, keloid conditions,scleroderma/systemic sclerosis, arthofibrosis, peyronie's disease,dupuytren's contracture, oral submucous fibrosis, or adhesivecapsulitis.

In another embodiment, the disclosure provides a method of treating adisease of bone density or lack of bone density using BCN512 or ananalog thereof. Examples include, osteoporosis, aging and lack of bonedensity, bone fracturing or breaking.

In another embodiment, the disclosure provides a method of treating thelack of hair growth or balding BCN512 or an analog thereof. Examplesinclude alopecia, loss of hair due to age or patterned baldness.

In another embodiment, the invention provides compounds represented byFormula I or a pharmaceutically acceptable salt, ester, or prodrugthereof:

wherein:A⁵ is a secondary or tertiary amine (i.e., thereby forming asulfonamide), andA⁶ is a substituted or unsubstituted aryl or heteroaryl group,preferably wherein the aryl or heteroaryl group bears at least onesubstituent including a nitro substituted, e.g., disposed at a positiondistal to the sulfonyl. In certain embodiments, A⁵ is a heterocyclicamine, such as a piperidine, piperazine, or morpholine ring, while inother embodiments, the amine is acyclic and/or the nitrogen atom boundto the sulfonyl is not included in any ring that may be present in A⁵.

Embodiments include a method of modulating Wnt activity to treat anailment in a subject, comprising administering to the subject atherapeutically effective amount of a compound having the structure ofFormula Ia. The ailment can be radiation exposure, fibrosis, insulinsensitivity, cancer, osteoporosis, alopecia/hair growth, wound healing,low bone density and/or obesity. The ailment can also be one or moreside effects of chemotherapy or radiotherapy.

In another embodiment, the invention provides compounds represented byFormula II or a pharmaceutically acceptable salt, ester or prodrugthereof:

whereinX is N or —C(H)—, preferably N;Y¹ and Y² are each independently lower alkyl or Y¹ and Y² taken togetherwith X form a heterocyclyl ring system, such as

wherein

X is N, C or CH; G is N, C or CH;

Z is absent or selected from substituted or unsubstituted alkyl,heteroalkyl, alkenyl, or alkynyl; andR⁴ is hydrogen or selected from substituted or unsubstituted aryl (e.g.,phenyl) and heteroaryl, andR⁵ and R⁶ are each independently absent or lower alkyl.

In other embodiments, X, Y¹ and Y² taken together form a ring system

wherein X is —C(H)—, andR⁴ is selected from substituted or unsubstituted aryl (e.g. phenyl) andheteroaryl, such as a halogen-substituted phenyl group, e.g.4-fluorophenyl or 3-chlorophenyl.In certain embodiments, Y¹ and Y² are each ethyl.In certain preferred embodiments, Y¹ and Y² taken together form apiperazine ring.In certain preferred embodiments, Z is absent.

Embodiments include a method of modulating Wnt activity to treat anailment in a subject, comprising administering to the subject atherapeutically effective amount of a compound having the structure ofFormula IIa. The ailment can be radiation exposure, fibrosis, insulinsensitivity, cancer, osteoporosis, alopecia/hair growth, wound healing,low bone density and obesity. The ailment can also be one or more sideeffects of chemotherapy or radiotherapy. The fibrosis can be identifiedas pulmonary fibrosis, idiopathic pulmonary fibrosis, acute respiratorydistress syndrome, cystic fibrosis, non-cystic fibrosis bronchiectasis,cirrhosis, liver fibrosis, endomyocardial fibrosis, old myocardialinfarction, atrial fibrosis, mediastinal fibrosis, myelofibrosis,retroperitoneal fibrosis, progressive massive fibrosis, nephrogenicsystemic fibrosis, Crohn's disease, gastrointestinal fibrosis, keloidconditions, scleroderma/systemic sclerosis, arthofibrosis, peyronie'sdisease, dupuytren's contracture, oral submucous fibrosis, liverfibrosis, gastrointestinal fibrosis, renal fibrosis from kidney dialysisor adhesive capsulitis

Another embodiment is a compound of Formula C or an analog thereof,

R₁=a halogen, N, OH, CH₃, OH, (CH₂)_(n)—CH₃ or substituted orunsubstituted aryl;R₂=a halogen, N, OH, CH₃, OH, (CH₂)_(n)—CH₃ or substituted orunsubstituted aryl;R₃=a halogen, N, OH, CH₃, OH, (CH₂)_(n)—CH₃ or substituted orunsubstituted aryl;R₄=a halogen, N, OH, CH₃, OH, (CH₂)_(n)—CH₃ or substituted orunsubstituted aryl.Analogs can include the compounds of Formula XXII, Formula XXIII,Formula XXIV, Formula XXV, Formula XXVI and Formula XXVII.

Embodiments also include a method of treating inflammation in a subjectwith a compound of Formula C or an analog thereof. The analog can beFormula XXII, Formula XXIII, Formula XXIV, Formula XXV, Formula XXVIand/or Formula XXVII.

Embodiments also include a method of modulating Wnt activity to treat anailment in a subject, comprising administering to the subject atherapeutically effective amount of a compound of Formula XXI or ananalog thereof. The analog can be Formula XXII, Formula XXIII, FormulaXXIV, Formula XXV, Formula XXVI and/or Formula XXVII. The ailment can beradiation exposure, fibrosis, insulin sensitivity, cancer, osteoporosis,alopecia/hair growth, wound healing, low bone density and/or obesity.The fibrosis can be pulmonary fibrosis, idiopathic pulmonary fibrosis,acute respiratory distress syndrome, cystic fibrosis, non-cysticfibrosis bronchiectasis, cirrhosis, liver fibrosis, endomyocardialfibrosis, old myocardial infarction, atrial fibrosis, mediastinalfibrosis, myelofibrosis, retroperitoneal fibrosis, progressive massivefibrosis, nephrogenic systemic fibrosis, Crohn's disease,gastrointestinal fibrosis, keloid conditions, scleroderma/systemicsclerosis, arthofibrosis, peyronie's disease, dupuytren's contracture,oral submucous fibrosis, liver fibrosis, gastrointestinal fibrosis,renal fibrosis from kidney dialysis or adhesive capsulitis.

In certain embodiments, compounds of the invention may be prodrugs ofthe compounds of formula I or II, e.g., wherein a hydroxyl in the parentcompound is presented as an ester or a carbonate, or carboxylic acidpresent in the parent compound is presented as an ester. In certain suchembodiments, the prodrug is metabolized to the active parent compound invivo (e.g., the ester is hydrolyzed to the corresponding hydroxyl, orcarboxylic acid).

In certain embodiments, compounds of the invention may be racemic. Incertain embodiments, compounds of the invention may be enriched in oneenantiomer. For example, a compound of the invention may have greaterthan 30% ee, 40% ee, 50% ee, 60% ee, 70% ee, 80% ee, 90% ee, or even 95%or greater ee. In certain embodiments, compounds of the invention mayhave more than one stereocenter. In certain such embodiments, compoundsof the invention may be enriched in one or more diastereomer. Forexample, a compound of the invention may have greater than 30% de, 40%de, 50% de, 60% de, 70% de, 80% de, 90% de, or even 95% or greater de.

In certain embodiments, the present invention relates to methods oftreatment with a compound of formula Ia, IIa, A, B, C, an analog and/ora pharmaceutically acceptable salt thereof. In certain embodiments, thetherapeutic preparation may be enriched to provide predominantly oneenantiomer of a compound (e.g., of formula Ia, IIa, A, B or C).

In certain embodiments, the therapeutic preparation may be enriched toprovide predominantly one diastereomer of a compound (e.g., of formulaIa, IIa, A, B or C). A diastereomerically enriched mixture may comprise,for example, at least 60 mol percent of one diastereomer, or morepreferably at least 75, 90, 95, or even 99 mol percent.

In certain embodiments, the present invention relates to methods oftreatment with a compound of formula Formula Ia, IIa, A, B or C, or apharmaceutically acceptable salt thereof. In certain embodiments, thetherapeutic preparation may be enriched to provide predominantly oneenantiomer of a compound (e.g. of formula Ia, IIa, A, B or C).

In certain embodiments, the therapeutic preparation may be enriched toprovide predominantly one diastereomer of a compound (e.g., of formulaFormula Ia, IIa, A, B or C). In certain embodiments, the presentinvention provides a pharmaceutical preparation suitable for use in ahuman patient, comprising any of the compounds shown above (e.g., acompound of the invention, such as a compound of Formula Ia, IIa, A, Bor C), and one or more pharmaceutically acceptable excipients. Incertain embodiments, the pharmaceutical preparations may be for use intreating or preventing a condition or disease as described herein, incertain embodiments, the pharmaceutical preparations have a low enoughpyrogen activity to be suitable for use in a human patient. Compounds ofany of the above structures may be used in the manufacture ofmedicaments for the treatment of any diseases or conditions disclosedherein.

Various other objects, features and attendant advantages of the presentinvention will become fully appreciated as the same becomes betterunderstood when considered in conjunction with the accompanyingdrawings, in which like reference characters designate the same orsimilar parts throughout the several views, and wherein:

BRIEF DESCRIPTION OF THE FIGURES

FIG. 1 shows the effects of 5-FU and BCN057 on the viability ofpancreatic cancer cell lines.

FIG. 2A shows the annexin V apoptosis and necrosis assay in Panc-1 cellsin a dose dependent manner.

FIG. 2B shows the annexin V apoptosis and necrosis assay in Panc-1 cellsover time.

FIG. 3A-3F show the effects of 10 uM BCN057 on the viability ofpancreatic cancer cell lines. FIG. 3A shows pancreatic cancer cell linesat time 0; FIG. 3B at 15 minutes; FIG. 3C at 30 minutes; FIG. 3D at 60minutes; FIG. 3E at 120 minutes; FIG. 3F at and 240 minutes.

FIG. 4A is a graph of the results of a viability assay on pancreaticcells FIG. 4B shows the data for each time point.

FIG. 5A depicts compound H.

FIG. 5B depicts compound K.

FIG. 6 is a graph that depicts fibrotic lesions in untreated lung tissuesections and sections treated with BCN512.

FIG. 7A-7F show the histopathology of lung sections stained for TGFβ inC57M Male mice receiving nothing (A), 14Gy thoracic radiation (B) orradiation and BCNB512 (C). Images D, E and F are cardiac muscle stainsunder the same parameters from the same animals.

Definitions

Reference in this specification to “one embodiment/aspect” or “anembodiment/aspect” means that a particular feature, structure, orcharacteristic described in connection with the embodiment/aspect isincluded in at least one embodiment/aspect of the disclosure. The use ofthe phrase “in one embodiment/aspect” or “in another embodiment/aspect”in various places in the specification are not necessarily all referringto the same embodiment/aspect, nor are separate or alternativeembodiments/aspects mutually exclusive of other embodiments/aspects.Moreover, various features are described which may be exhibited by someembodiments/aspects and not by others. Similarly, various requirementsare described which may be requirements for some embodiments/aspects butnot other embodiments/aspects. Embodiment and aspect can be in certaininstances be used interchangeably.

The terms used in this specification generally have their ordinarymeanings in the art, within the context of the disclosure, and in thespecific context where each term is used. Certain terms that are used todescribe the disclosure are discussed below, or elsewhere in thespecification, to provide additional guidance to the practitionerregarding the description of the disclosure. It will be appreciated thatthe same thing can be said in more than one way.

Consequently, alternative language and synonyms may be used for any oneor more of the terms discussed herein. Nor is any special significanceto be placed upon whether or not a term is elaborated or discussedherein. Synonyms for certain terms are provided. A recital of one ormore synonyms does not exclude the use of other synonyms. The use ofexamples anywhere in this specification including examples of any termsdiscussed herein is illustrative only, and is not intended to furtherlimit the scope and meaning of the disclosure or of any exemplifiedterm. Likewise, the disclosure is not limited to various embodimentsgiven in this specification.

Without intent to further limit the scope of the disclosure, examples ofinstruments, apparatus, methods and their related results according tothe embodiments of the present disclosure are given below. Note thattitles or subtitles may be used in the examples for convenience of areader, which in no way should limit the scope of the disclosure. Unlessotherwise defined, all technical and scientific terms used herein havethe same meaning as commonly understood by one of ordinary skill in theart to which this disclosure pertains. In the case of conflict, thepresent document, including definitions, will control.

Unless otherwise indicated, all numbers expressing a characteristic,item, quantity, parameter, property, term, and so forth used in thepresent specification and claims are to be understood as being modifiedin all instances by the term “about.” As used herein, the term “about”means that the characteristic, item, quantity, parameter, property, orterm so qualified encompasses a range of plus or minus ten percent aboveand below the value of the stated characteristic, item, quantity,parameter, property, or term. Accordingly, unless indicated to thecontrary, the numerical parameters set forth in the specification andattached claims are approximations that may vary. For instance, as massspectrometry instruments can vary slightly in determining the mass of agiven analyte, the term “about” in the context of the mass of an ion orthe mass/charge ratio of an ion refers to +/−0.50 atomic mass unit. Atthe very least, and not as an attempt to limit the application of thedoctrine of equivalents to the scope of the claims, each numericalindication should at least be construed in light of the number ofreported significant digits and by applying ordinary roundingtechniques.

Use of the terms “may” or “can” in reference to an embodiment or aspectof an embodiment also carries with it the alternative meaning of “maynot” or “cannot.” As such, if the present specification discloses thatan embodiment or an aspect of an embodiment may be or can be included aspart of the inventive subject matter, then the negative limitation orexclusionary proviso is also explicitly meant, meaning that anembodiment or an aspect of an embodiment may not be or cannot beincluded as part of the inventive subject matter. In a similar manner,use of the term “optionally” in reference to an embodiment or aspect ofan embodiment means that such embodiment or aspect of the embodiment maybe included as part of the inventive subject matter or may not beincluded as part of the inventive subject matter. Whether such anegative limitation or exclusionary proviso applies will be based onwhether the negative limitation or exclusionary proviso is recited inthe claimed subject matter.

Notwithstanding that the numerical ranges and values setting forth thebroad scope of the disclosure are approximations, the numerical rangesand values set forth in the specific examples are reported as preciselyas possible. Any numerical range or value, however, inherently containscertain errors necessarily resulting from the standard deviation foundin their respective testing measurements. Recitation of numerical rangesof values herein is merely intended to serve as a shorthand method ofreferring individually to each separate numerical value falling withinthe range. Unless otherwise indicated herein, each individual value of anumerical range is incorporated into the present specification as if itwere individually recited herein.

The terms “a,” “an,” “the” and similar references used in the context ofdescribing the present disclosure (especially in the context of thefollowing claims) are to be construed to cover both the singular and theplural, unless otherwise indicated herein or clearly contradicted bycontext. Further, ordinal indicators—such as “first,” “second,” “third,”etc.—for identified elements are used to distinguish between theelements, and do not indicate or imply a required or limited number ofsuch elements, and do not indicate a particular position or order ofsuch elements unless otherwise specifically stated. All methodsdescribed herein can be performed in any suitable order unless otherwiseindicated herein or otherwise clearly contradicted by context. The useof any and all examples, or exemplary language (e.g., “such as”)provided herein is intended merely to better illuminate the presentdisclosure and does not pose a limitation on the scope of the disclosureotherwise claimed. No language in the present specification should beconstrued as indicating any non-claimed element essential to thepractice of the disclosure.

When used in the claims, whether as filed or added per amendment, theopen-ended transitional term “comprising” (and equivalent open-endedtransitional phrases thereof like including, containing and having)encompasses all the expressly recited elements, limitations, stepsand/or features alone or in combination with unrecited subject matter;the named elements, limitations and/or features are essential, but otherunnamed elements, limitations and/or features may be added and stillform a construct within the scope of the claim. Specific embodimentsdisclosed herein may be further limited in the claims using theclosed-ended transitional phrases “consisting of” or “consistingessentially of” in lieu of or as an amended for “comprising.” When usedin the claims, whether as filed or added per amendment, the closed-endedtransitional phrase “consisting of” excludes any element, limitation,step, or feature not expressly recited in the claims. The closed-endedtransitional phrase “consisting essentially of” limits the scope of aclaim to the expressly recited elements, limitations, steps and/orfeatures and any other elements, limitations, steps and/or features thatdo not materially affect the basic and novel characteristic(s) of theclaimed subject matter. Thus, the meaning of the open-ended transitionalphrase “comprising” is being defined as encompassing all thespecifically recited elements, limitations, steps and/or features aswell as any optional, additional unspecified ones. The meaning of theclosed-ended transitional phrase “consisting of” is being defined asonly including those elements, limitations, steps and/or featuresspecifically recited in the claim whereas the meaning of theclosed-ended transitional phrase “consisting essentially of” is beingdefined as only including those elements, limitations, steps and/orfeatures specifically recited in the claim and those elements,limitations, steps and/or features that do not materially affect thebasic and novel characteristic(s) of the claimed subject matter.Therefore, the open-ended transitional phrase “comprising” (andequivalent open-ended transitional phrases thereof) includes within itsmeaning, as a limiting case, claimed subject matter specified by theclosed-ended transitional phrases “consisting of” or “consistingessentially of.” As such embodiments described herein or so claimed withthe phrase “comprising” are expressly or inherently unambiguouslydescribed, enabled and supported herein for the phrases “consistingessentially of” and “consisting of.”

As applicable, the terms “about” or “generally”, as used herein in thespecification and appended claims, and unless otherwise indicated, meansa margin of +/−20%. Also, as applicable, the term “substantially” asused herein in the specification and appended claims, unless otherwiseindicated, means a margin of +/−10%. It is to be appreciated that notall uses of the above terms are quantifiable such that the referencedranges can be applied.

The term “active agent” or “active ingredient” refers to a substance,compound, or molecule, which is biologically active or otherwise,induces a biological or physiological effect on a subject to which it isadministered to. In other words, “active agent” or “active ingredient”refers to a component or components of a composition to which the wholeor part of the effect of the composition is attributed. An active agentcan be a primary active agent, or in other words, the component(s) of acomposition to which the whole or part of the effect of the compositionis attributed. An active agent can be a secondary agent, or in otherwords, the component(s) of a composition to which an additional partand/or other effect of the composition is attributed.

The term “cancer” can include one or more of Adenoid Cystic Carcinoma,Adrenal Gland Cancer, Amyloidosis, Anal Cancer, Ataxia-Telangiectasia,Atypical Mole Syndrome, Basal Cell Carcinoma, Bile Duct Cancer, BirtHogg Dube Syndrome, Bladder Cancer, Bone Cancer, Brain Tumor, BreastCancer, Breast Cancer in Men, Carcinoid Tumor, Cervical Cancer,Colorectal Cancer, Ductal Carcinoma, Endometrial Cancer, EsophagealCancer, Gastric Cancer, Gastrointestinal Stromal Tumor (GIST),HER2-Positive Breast Cancer, Islet Cell Tumor, Juvenile PolyposisSyndrome, Kidney Cancer, Laryngeal Cancer, Leukemia-Acute LymphoblasticLeukemia, Leukemia -Acute Lymphocytic (ALL), Leukemia-Acute Myeloid AML,Leukemia-Adult, Leukemia - Childhood, Leukemia - Chronic Lymphocytic -CLL, Leukemia - Chronic Myeloid -CML, Liver Cancer, Lobular Carcinoma,Lung Cancer, Lung Cancer - Small Cell, Lymphoma - Hodgkin's, Lymphoma -Non-Hodgkin's, Malignant Glioma, Melanoma, Meningioma, Multiple Myeloma,Myelodysplastic Syndrome (MDS), Nasopharyngeal Cancer, NeuroendocrineTumor, Oral Cancer, Osteosarcoma, Ovarian Cancer, Pancreatic Cancer,Pancreatic Neuroendocrine Tumors, Parathyroid Cancer, Penile Cancer,Peritoneal Cancer, Peutz-Jeghers Syndrome, Pituitary Gland Tumor,Polycythemia Vera, Prostate Cancer, Renal Cell Carcinoma,Retinoblastoma, Salivary Gland Cancer, Sarcoma, Sarcoma - Kaposi, SkinCancer, Small Intestine Cancer, Stomach Cancer, Testicular Cancer,Thymoma, Thyroid Cancer, Uterine (Endometrial) Cancer, Vaginal Cancerand Wilms' Tumor. The term “blood cancer” can include one or more ofleukemia, lymphoma, myeloma, myelodysplastic syndromes andmyeloproliferative neoplasms.

The term “derivative” can refer to any compound having the same or asimilar core structure to the compound but having at least onestructural difference, including substituting, deleting, and/or addingone or more atoms or functional groups. The term “derivative” does notmean that the derivative is synthesized from the parent compound eitheras a starting material or intermediate, although this may be the case.The term “derivative” can include prodrugs, or metabolites of the parentcompound. Derivatives include compounds in which carboxyl groups in theparent compound have been derivatized to form methyl and ethyl esters,or other types of esters or hydrazides. Derivatives include compounds inwhich hydroxyl groups in the parent compound have been derivatized toform O-acyl or O-alkyl derivatives. Derivatives include compounds inwhich a hydrogen bond donating group in the parent compound is replacedwith another hydrogen bond donating group such as OH, NH, or SH.Derivatives include replacing a hydrogen bond acceptor group in theparent compound with another hydrogen bond acceptor group such asesters, ethers, ketones, carbonates, tertiary amines, imine, thiones,sulfones, tertiary amides, and sulfides. Derivatives can also includethe salt forms, such as pharmaceutically acceptable salt forms of aparent compound or derivative thereof.

The term “fibrosis” refers to a condition with the formation of excessfibrous connective tissue in an organ or tissue in a reparative orreactive process. This can be a reactive, benign, or pathological state.

As used herein, “mitigating” means reducing one or more negativesymptoms of a condition, relative to a cell, organ, tissue, or organismdisplaying the symptom or condition for the same amount of time, butuntreated.

In some embodiments, contacting the cell, organ, tissue, or organism thepresent compounds may comprise administering a therapeutically effectiveamount of the compound to a subject. As used herein, a “therapeuticallyeffective amount” is an amount sufficient to mitigate the negativesymptom or condition.

The term “subject” or “patient” refers to any single animal, morepreferably a mammal (including such non-human animals as, for example,dogs, cats, horses, rabbits, zoo animals, cows, pigs, sheep, andnon-human primates) for which treatment is desired. Most preferably, thepatient herein is a human.

The term “pharmaceutically acceptable carrier” as used herein refers toany and all solvents, dispersion media, coatings, isotonic andabsorption delaying agents, and the like, that are compatible withpharmaceutical administration. The use of such media and agents forpharmaceutically active substances is well known in the art. Thecompositions may also contain other active compounds providingsupplemental, additional, or enhanced therapeutic functions.

The term “pharmaceutically acceptable composition” as used herein refersto a composition comprising at least one compound as disclosed hereinformulated together with one or more pharmaceutically acceptablecarriers.

The term “pharmaceutically acceptable prodrugs” as used hereinrepresents those prodrugs of the compounds of the present disclosurethat are, within the scope of sound medical judgment, suitable for usein contact with the tissues of humans and lower animals without unduetoxicity, irritation, allergic response, commensurate with a reasonablebenefit/risk ratio, and effective for their intended use, as well as thezwitterionic forms, where possible, of the compounds of the presentdisclosure. A discussion is provided in Higuchi et al., “Prodrugs asNovel Delivery Systems,” ACS Symposium Series, Vol. 14, and in Roche, E.B., ed. Bioreversible Carriers in Drug Design, American PharmaceuticalAssociation and Pergamon Press, 1987, both of which are incorporatedherein by reference.

The term “pharmaceutically acceptable salt(s)” refers to salts of acidicor basic groups that may be present in compounds used in the presentcompositions. Compounds included in the present compositions that arebasic in nature are capable of forming a wide variety of salts withvarious inorganic and organic acids. The acids that may be used toprepare pharmaceutically acceptable acid addition salts of such basiccompounds are those that form non-toxic acid addition salts, i.e., saltscontaining pharmacologically acceptable anions, including but notlimited to sulfate, citrate, matate, acetate, oxalate, chloride,bromide, iodide, nitrate, sulfate, bisulfate, phosphate, acid phosphate,isonicotinate, acetate, lactate, salicylate, citrate, tartrate, oleate,tannate, pantothenate, bitartrate, ascorbate, succinate, maleate,gentisinate, fumarate, gluconate, glucaronate, saccharate, formate,benzoate, glutamate, methanesulfonate, ethanesulfonate,benzenesulfonate, p-toluenesulfonate and pamoate (i.e.,1,1′-methylene-bis-(2-hydroxy-3-naphthoate)) salts. Compounds includedin the present compositions that include an amino moiety may formpharmaceutically acceptable salts with various amino acids, in additionto the acids mentioned above. Compounds included in the presentcompositions, that are acidic in nature are capable of forming basesalts with various pharmacologically acceptable cations. Examples ofsuch salts include alkali metal or alkaline earth metal salts and,particularly, calcium, magnesium, sodium, lithium, zinc, potassium, andiron salts.

The term “chemotherapy” refers to a type of cancer treatment that usesone or more anti-cancer drugs (i.e. chemotherapeutic agents).Chemotherapy can be given with a curative intent (typically withcombinations of drugs), or it can be used to prolong life or to reducesymptoms (i.e. palliative chemotherapy). Conventional chemotherapeuticagents are cytotoxic by means of interfering with cell division(mitosis). Common side effects of chemotherapy include myelosuppression,mucositis (inflammation of the lining of the digestive tract) andalopecia.

The term “KRAS” refers to a gene that acts as an “on/off” switch in cellsignaling. When it functions normally, it controls cell proliferation.It can be allosterically activated and recruits and activates proteinsnecessary for the propagation of growth factors, along with other cellsignaling receptors such as c-Raf and PI 3-kinase. Negative signalingcan be disrupted when it is mutated causing cells to over-proliferateand develop into cancer.

The terms “polypeptide,” “peptide” and “protein” are usedinterchangeably herein to refer to a polymer of amino acid residues. Theterms apply to amino acid polymers in which one or more amino acidresidue is an artificial chemical mimetic of a corresponding naturallyoccurring amino acid, as well as to naturally occurring amino acidpolymers and non-naturally occurring amino acid polymer. Methods forobtaining (e.g., producing, isolating, purifying, synthesizing, andrecombinantly manufacturing) polypeptides are well known to one ofordinary skill in the art.

The term “RIGS” or “radiation-induced gastrointestinal syndrome” resultsfrom a combination of direct cytocidal effects of irradiation onintestinal crypt cells and stromal cells with loss of the mucosalbarrier and symptoms ranging from diarrhea, electrolyte imbalance,weight loss and death. A significant proportion of patients experienceradiation-induced toxicity due to damage to normal tissue in theirradiation field. The use of chemical or biological approaches aimed atreducing or preventing normal tissue toxicity induced by radiotherapy isa long-held goal.

The term “radiation therapy” or “radio therapy” refers to a therapyusing ionizing radiation, generally as part of cancer treatment tocontrol or kill malignant cells. Radiation therapy is commonly appliedto the cancerous tumor because of its ability to control cell growth.Ionizing radiation works by damaging the DNA of cancerous tissue leadingto cellular death. The main side effects are fatigue and skinirritation. Acute side effects can include nausea and vomiting, damageto the epithelial surfaces, mouth, throat and stomach sores, swelling,intestinal discomfort. RIGS (radiation induced gastrointestinalsyndrome) is a common term used to describe side effect related to thegastrointestinal system.

The term “SFRP” or “secreted frizzled-related protein” refers to a Wntsignaling pathway inhibitor which is part of the solublefrizzled-related proteins (sFRPS). sFRPS function as modulators of Wntsignaling through direct interaction with Wnts. Five mammalian sFRPshave been identified (sFRP-1, sFRP-2, sFRP-3, sFRP-4 and sFRP-5). Theseproteins consist of approximately 300 amino acids containing a signalsequence, a Frizzled-like cysteine-rich domain (CRD), and a smallhydrophilic C-terminal domain. As a group, sFRPs are expressed in avariety of embryonic and adult tissues, suggesting a common mechanismfor inhibiting Wnt signaling. Individual family members, however, havespecific spatial and temporal expression patterns.

The term “Wnt signaling pathways” refers to a group of signaltransduction pathways which begin with proteins that pass signals into acell through cell surface receptors. The canonical Wnt pathway leads toregulation of gene transcription.

The term “treating” or “treatment” refers to one or more of (1)inhibiting the disease; e.g., inhibiting a disease, condition ordisorder in an individual who is experiencing or displaying thepathology or symptomatology of the disease, condition or disorder (i.e.,arresting further development of the pathology and/or symptomatology);and (2) ameliorating the disease; e.g., ameliorating a disease,condition or disorder in an individual who is experiencing or displayingthe pathology or symptomatology of the disease, condition or disorder(i.e., reversing the pathology and/or symptomatology) such as decreasingthe severity of disease. Treatment can be prophylactic and/ortherapeutic. The term “prophylactic or therapeutic” treatment isart-recognized and includes administration to the host of one or more ofthe subject compositions. If it is administered prior to clinicalmanifestation of the unwanted condition (e.g., disease or other unwantedstate of the host animal) then the treatment is prophylactic (i.e., itprotects the host against developing the unwanted condition), whereas ifit is administered after manifestation of the unwanted condition, thetreatment is therapeutic (i.e., it is intended to diminish, ameliorate,or stabilize the existing unwanted condition or side effects thereof).

The term “TOPFLASH” or “TCF/LEF reporter kit” refers to a kit formonitoring the activity of Wnt/β-catenin signaling pathway in thecultured cells. The kit typically includes a TCF/LEF luciferase reportervector which is a Wnt pathway-responsive reporter.

The term “unit dosage form” or “unit” as used herein refers tophysically discrete units suitable as unitary dosages for human andanimal subjects, each unit containing a predetermined quantity of thecompound calculated in an amount sufficient to produce the desiredeffect in association with a pharmaceutically acceptable, diluent,carrier or vehicle. The specifications for the novel unit dosage formsof the present disclosure depend on the particular compound employed andthe effect to be achieved, and the pharmacodynamics associated with eachcompound in the subject.

The compounds of the disclosure may contain one or more chiral centersand/or double bonds and, therefore, exist as stereoisomers, such asgeometric isomers, enantiomers or diastereomers. The term“stereoisomers” when used herein consist of all geometric isomers,enantiomers or diastereomers. These compounds may be designated by thesymbols “R” or “S,” depending on the configuration of substituentsaround the stereogenic carbon atom. The present disclosure encompassesvarious stereoisomers of these compounds and mixtures thereof.Stereoisomers include enantiomers and diastereomers. Mixtures ofenantiomers or diastereomers may be designated “(±)” in nomenclature,but the skilled artisan will recognize that a structure may denote achiral center implicitly.

Individual stereoisomers of compounds of the present disclosure can beprepared synthetically from commercially available starting materialsthat contain asymmetric or stereogenic centers, or by preparation ofracemic mixtures followed by resolution methods well known to those ofordinary skill in the art. These methods of resolution are exemplifiedby (1) attachment of a mixture of enantiomers to a chiral auxiliary,separation of the resulting mixture of diastereomers byrecrystallization or chromatography and liberation of the optically pureproduct from the auxiliary, (2) salt formation employing an opticallyactive resolving agent, or (3) direct separation of the mixture ofoptical enantiomers on chiral chromatographic columns. Stereoisomericmixtures can also be resolved into their component stereoisomers bywell-known methods, such as chiral-phase gas chromatography,chiral-phase high performance liquid chromatography, crystallizing thecompound as a chiral salt complex, or crystallizing the compound in achiral solvent. Stereoisomers can also be obtained fromstereomerically-pure intermediates, reagents, and catalysts bywell-known asymmetric synthetic methods.

Geometric isomers can also exist in the compounds of the presentdisclosure. The present disclosure encompasses the various geometricisomers and mixtures thereof resulting from the arrangement ofsubstituents around a carbon-carbon double bond or arrangement ofsubstituents around a carbocyclic ring. Substituents around acarbon-carbon double bond are designated as being in the “Z” or “E”configuration wherein the terms “Z” and “E” are used in accordance withIUPAC standards. Unless otherwise specified, structures depicting doublebonds encompass both the E and Z isomers.

Substituents around a carbon-carbon double bond alternatively can bereferred to as “cis” or “trans,” where “cis” represents substituents onthe same side of the double bond and “trans” represents substituents onopposite sides of the double bond. The arrangements of substituentsaround a carbocyclic ring are designated as “cis” or “trans.” The term“cis” represents substituents on the same side of the plane of the ringand the term “trans” represents substituents on opposite sides of theplane of the ring. Mixtures of compounds wherein the substituents aredisposed on both the same and opposite sides of plane of the ring aredesignated “cis/trans.”

The compounds disclosed herein may exist as tautomers and bothtautomeric forms are intended to be encompassed by the scope of thepresent disclosure, even though only one tautomeric structure isdepicted.

The term “alkoxy” represents a chemical substituent of formula —OR,where R is an optionally substituted C₁-C₆ alkyl group, unless otherwisespecified. In some embodiments, the alkyl group can be substituted,e.g., the alkoxy group can have 1, 2, 3, 4, 5 or 6 substituent groups asdefined herein.

The term “alkoxyalkyl” represents a heteroalkyl group, as definedherein, that is described as an alkyl group that is substituted with analkoxy group. Exemplary unsubstituted alkoxyalkyl groups include between2 to 12 carbons. In some embodiments, the alkyl and the alkoxy each canbe further substituted with 1, 2, 3, or 4 substituent groups as definedherein for the respective group.

The terms “alkyl,” “alkenyl” and “alkynyl” include straight-chain,branched-chain and cyclic monovalent substituents, as well ascombinations of these, containing only C and H when unsubstituted.Examples include methyl, ethyl, isobutyl, cyclohexyl, cyclopentylethyl,2-propenyl, 3-butynyl, and the like. The term “cycloalkyl,” as usedherein, represents a monovalent saturated or unsaturated non-aromaticcyclic alkyl group having between three to nine carbons (e.g., a C3-C9cycloalkyl), unless otherwise specified, and is exemplified bycyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl,bicyclo[2.2.1.]heptyl, and the like. When the cycloalkyl group includesone carbon-carbon double bond, the cycloalkyl group can be referred toas a “cycloalkenyl” group. Exemplary cycloalkenyl groups includecyclopentenyl, cyclohexenyl, and the like. Typically, the alkyl, alkenyland alkynyl groups contain 1-12 carbons (e.g., C₁-C₁₂ alkyl) or 2-12carbons (e.g., C₂-C₁₂ alkenyl or C₂-C₁₂ alkynyl). In some embodiments,the alkyl groups are C₁-C₈, C₁-C₆, C₁-C₄, C₁-C₃, or C₁-C₂ alkyl groups;or C₂-C₈, C₂-C₆, C₂-C₄, or C₂-C₃ alkenyl or alkynyl groups. Further, anyhydrogen atom on one of these groups can be replaced with a substituentas described herein.

Heteroalkyl, heteroalkenyl and heteroalkynyl are similarly defined andcontain at least one carbon atom but also contain one or more 0, S or Nheteroatoms or combinations thereof within the backbone residue wherebyeach heteroatom in the heteroalkyl, heteroalkenyl or heteroalkynyl groupreplaces one carbon atom of the alkyl, alkenyl or alkynyl group to whichthe heteroform corresponds. In some embodiments, the heteroalkyl,heteroalkenyl and heteroalkynyl groups have C at each terminus to whichthe group is attached to other groups, and the heteroatom(s) present arenot located at a terminal position. As is understood in the art, theseheteroforms do not contain more than three contiguous heteroatoms. Insome embodiments, the heteroatom is O or N. The term “heterocyclyl,” asused herein represents cyclic heteroalkyl or heteroalkenyl that is,e.g., a 3-, 4-, 5-, 6- or 7-membered ring, unless otherwise specified,containing one, two, three, or four heteroatoms independently selectedfrom the group consisting of nitrogen, oxygen, and sulfur. The5-membered ring has zero to two double bonds, and the 6- and 7- memberedrings have zero to three double bonds. The term “heterocyclyl” alsorepresents a heterocyclic compound having a bridged multicyclicstructure in which one or more carbons and/or heteroatoms bridges twonon-adjacent members of a monocyclic ring, e.g., a quinuclidinyl group.The term “heterocyclyl” includes bicyclic, tricyclic, and tetracyclicgroups in which any of the above heterocyclic rings is fused to one,two, or three carbocyclic rings, e.g., an aryl ring, a cyclohexane ring,a cyclohexene ring, a cyclopenlane ring, a cyclopentene ring, or anothermonocyclic heterocyclic ring, such as indolyl, quinolyl, isoquinolyl,tetrahydroquinolyl, benzofuryl, benzothienyl and the like.

The term “alkylsulfonyl,” as used herein, represents a heteroalkyl groupthat is described as an optionally substituted alkyl group, as describedherein, that includes an —S(O)₂— group.

The term “amino,” as used herein, represents—N(R)₂, wherein each R is,independently, H, OH, NO₂, N(R)₂, SO₂OR, SO₂R, SOR, SO₂N(R)₂, SON(R)₂,an N-protecting group, alkyl, alkenyl, alkynyl, alkoxy, aryl, alkaryl,cycloalkyl, alkcycloalkyl, heterocyclyl (e.g., heteroaryl),alkheterocyclyl (e.g., alkheteroaryl), or two R combine to form aheterocyclyl or an N-protecting group, and wherein each R^(N2) is,independently, H, alkyl, or aryl. In a preferred embodiment, amino is—NH₂, or —NHR, wherein R is, independently, OH, NO₂, NH₂, NR₂, SO₂OR,SO₂R, SOR, SO₂N(R)₂, SON(R)₂, alkyl, or aryl, and each R can be H,alkyl, or aryl. The term “aminoalkyl,” as used herein, represents aheteroalkyl group, as defined herein, that is described as an alkylgroup, as defined herein, substituted by an amino group, as definedherein. The alkyl and amino each can be further substituted with 1, 2,3, or 4 substituent groups as described herein for the respective group.For example, the alkyl moiety may comprise an oxo (═O) substituent.

“Aromatic” moiety or “aryl” moiety refers to any monocyclic or fusedring bicyclic system which has the characteristics of aromaticity interms of electron distribution throughout the ring system and includes amonocyclic or fused bicyclic moiety such as phenyl or naphthyl;“heteroaromatic” or “heteroaryl” also refers to such monocyclic or fusedbicyclic ring systems containing one or more heteroatoms selected fromO, S and N. The inclusion of a heteroatom permits inclusion of5-membered rings to be considered aromatic as well as 6-membered rings.Thus, typical aromatic/heteroaromatic systems include pyridyl,pyrimidyl, indolyl, benzimidazolyl, benzotriazolyl, isoquinolyl,quinolyl, benzothiazolyl, benzofuranyl, thienyl, furyl, pyrrolyl,thiazolyl, oxazolyl, isoxazolyl, benzoxazolyl, benzoisoxazolyl,imidazolyl and the like. Because tautomers are theoretically possible,phthalimido is also considered aromatic. Typically, the ring systemscontain 5-12 ring member atoms or 6-10 ring member atoms. In someembodiments, the aromatic or heteroaromatic moiety is a 6-memberedaromatic rings system optionally containing 1-2 nitrogen atoms. Moreparticularly, the moiety is an optionally substituted phenyl, pyridyl,indolyl, pyrimidyl, pyridazinyl, benzothiazolyl or benzimidazolyl,pyrazolyl, imidazolyl, isoxazolyl, thiazolyl, benzothiazolyl, indolyl.Even more particularly, such moiety is phenyl, pyridyl, or pyrimidyl andeven more particularly, it is phenyl. “O-aryl” or “O-heteroaryl” refersto aromatic or heteroaromatic systems which are coupled to anotherresidue through an oxygen atom. A typical example of an O-aryl isphenoxy. Similarly, “arylalkyl” refers to aromatic and heteroaromaticsystems which are coupled to another residue through a carbon chain,saturated or unsaturated, typically of C₁-C₂, C₁-C₆, or moreparticularly C₁-C₄ or C₁-C₃ when saturated or C₂-C₈, C₂-C₆, C₂-C₄, orC₂-C₃ when unsaturated, including the heteroforms thereof. For greatercertainty, arylalkyl thus includes an aryl or heteroaryl group asdefined above connected to an alkyl, heteroalkyl, alkenyl,heteroalkenyl, alkynyl or heteroalkynyl moiety also as defined above.Typical arylalkyls would be an aryl(C₆-C₁₂)alkyl(C₁-C₈),aryl(C₆-C₁₂)alkenyl(C₂-C₈), or aryl(C₆-C₁₂)alkynyl(C₂-C₈), plus theheteroforms. A typical example is phenylmethyl, commonly referred to asbenzyl.

Halo may be any halogen atom, especially F, Cl, Br, or I, and moreparticularly it is fluoro or chloro.

The term “haloalkyl,” as used herein, represents an alkyl group, asdefined herein, substituted by a halogen group (i.e., F, Cl, Br, or I).A haloalkyl may be substituted with one, two, three, or, in the case ofalkyl groups of two carbons or more, four halogens. Haloalkyl groupsinclude perfluoroalkyls. In some embodiments, the haloalkyl group can befurther substituted with 1, 2, 3, or 4 substituent groups as describedherein for alkyl groups.

The term “hydroxy,” as used herein, represents an —OH group.

The term “hydroxyalkyl,” as used herein, represents an alkyl group, asdefined herein, substituted by one to three hydroxy groups, with theproviso that no more than one hydroxy group may be attached to a singlecarbon atom of the alkyl group, and is exemplified by hydroxymethyl,dihydroxypropyl, and the like.

In general, a substituent group (e.g., alkyl, alkenyl, alkynyl, or aryl(including all heteroforms defined above) may itself optionally besubstituted by additional substituents. The nature of these substituentsis similar to those recited with regard to the substituents on the basicstructures above. Thus, where an embodiment of a substituent is alkyl,this alkyl may optionally be substituted by the remaining substituentslisted as substituents where this makes chemical sense, and where thisdoes not undermine the size limit of alkyl per se; e.g., alkylsubstituted by alkyl or by alkenyl would simply extend the upper limitof carbon atoms for these embodiments, and is not included. For example,where a group is substituted, the group may be substituted with 1, 2, 3,4, 5, or 6 substituents. Optional substituents include, but are notlimited to: C₁-C₆ alkyl or heteroaryl, C₂-C₆ alkenyl or heteroalkenyl,C₂-C₆ alkynyl or heteroalkynyl, halogen; aryl, heteroaryl, azido(—N₃),nitro (—NO₂), cyano (—CN), acyloxy (—OC(═O)R′), acyl (—C(═O)R′), alkoxy(—OR′), amido (—NR′C(═O)R″ or —C(═O)NR′R″), amino (—NR′R″), carboxylicacid (—CO₂H), carboxylic ester (—CO₂R′), carbamoyl (—OC(═O)NR′R″or—NRC(═O)OR′), hydroxy (—OH), isocyano (—NC), sulfonate (—S(═OHOR),sulfonamide (—S(═OHNRR′ or —NRS(═O)₂R′), or sulfonyl (—S(═O)₂R), whereeach R or R′ is selected, independently, from H, C₁-C₆ alkyl orheteroaryl, C₂-C₆ alkenyl or heteroalkenyl, C₂-C₆ alkynyl orheteroalkynyl, aryl, or heteroaryl. A substituted group may have, forexample, 1, 2, 3, 4, 5, 6, 7, 8, or 9 substituents.

Typical optional substituents include independently halo, CN, NO₂, CF₃,OCF₃, COOR, CONR₂ ^(Y), OR, SR, SOR, SO₂R, NR₂, NR(CO)R, NRC(O)OR,NRC(O)NR₂, NRSO₂NR₂, or NRSO₂R, wherein each R is independently H or anoptionally substituted group selected from alkyl, alkenyl, alkynyl,heteroalkyl, heteroalkenyl, heteroalkynyl, heteroaryl, and aryl (all asdefined above); or the substituent may be an optionally substitutedgroup selected from alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl,heteroalkynyl, aryl, heteroaryl, O-aryl, O-heteroaryl and arylalkyl.

Other technical terms used herein have their ordinary meaning in the artthat they are used, as exemplified by a variety of technicaldictionaries. The particular values and configurations discussed inthese non-limiting examples can be varied and are cited merely toillustrate at least one embodiment and are not intended to limit thescope thereof.

DETAILED DESCRIPTION

It is to be understood that both the foregoing general description andthe following detailed description are exemplary and explanatory and areintended to provide further explanation of the subject technology asclaimed. Additional features and advantages of the subject technologyare set forth in the description below, and in part will be apparentfrom the description, or may be learned by practice of the subjecttechnology. The advantages of the subject technology will be realizedand attained by the structure particularly pointed out in the writtendescription and claims hereof.

BCN057 and Analogs

BCN057, also known as YEL002, is represented by the following structure:

It can also be described as(3-[(Furan-2-ylmethyl)-amino]-2-(7-methoxy-2-oxo-1,2-dihydro-quinolin-3-yl)-6-methyl-imidazo[1,2-a]pyridin-1-ium).It will be appreciated that the invention covers compounds of BCN057,analogues and salts thereof. In one embodiment, the invention relates tocompounds of BCN057 in the form of a free base. In another embodiment,the invention relates to compounds of BCN057 or a pharmaceuticallyacceptable salt thereof.

Because of their potential use in medicine, salts of the compound ofBCN057 may be preferred as pharmaceutically acceptable salts. Suitablepharmaceutically acceptable salts can include acid addition salts. Apharmaceutically acceptable salt can be readily prepared by using adesired acid or base as appropriate. The resultant salt can precipitatefrom solution and be collected by filtration or recovered by evaporationof the solvent. The compound can exist as a stereoisomer, tautomer,pharmaceutical acceptable salt, or hydrate thereof. Some analogs ofBCN057 are presented below.

Embodiments include methods of treatment that include administering atherapeutically effective amount of a compound having the structure ofFormula B:

wherein:

R¹ is an alkyl, alkyl amine, or an ether;

R² is H or CH₃; and

R³ is H or OH.

In some embodiments, the compound is an analog selected from FormulaII-XIX, including Compound H, Compound K, Compound BNB-1, CompoundBNB-2, Compound BNB-3, Compound BNB-4 and Compound BNB-5.

BCN057 (Formula I) Analogs Name

Formula II

Formula III

Formula IV

Formula V

Formula VI

Formula VII

Formula VIII

Formula IX

Formula X

Formula XI

Formula XII

Formula XIII (Com- pound H)

Formula XIV (Com- pound K)

Formula XV (Com- pound BNB-1)

Formula XVI (Com- pound BNB-2)

Formula XVII (Com- pound BNB-3)

Formula XVIII (Com- pound BNB-4)

Formula XIX (Com- pound BNB-5)

BGN512 and Analogs

The structure of compound BGN512 is shown below as Formula XXI, alsoknown as 1-[(4-nitrobenezene)sulfonyl]-4-phenyl piperazine.

In some embodiments, the compound is an analog selected from FormulaXXII-XXV II.

BCN512 Analogs Name

Formula XXII (BCN52A1)

Formula XXIII

Formula XXIV

Formula XXV

Formula XXVI

Formula XXVII

Formula XXVIII

A compound of Formula I-XXVIII or analogs thereof disclosed herein canbe prepared according to established methodology in the art of organicsynthesis.

General methods of synthesizing the compound can be found in, e.g.,Stuart Warren and Paul Wyatt, Workbook for Organic Synthesis: TheDisconnection Approach, second Edition, Wiley, 2010. Exemplary methodsof making the compound is provided in U.S. patent application Ser. No.13/813,923 and U.S. patent application Ser. No. 14/889,719, hereinincorporated by reference. The compounds also include pharmaceuticallyacceptable salts thereof, prodrugs thereof, hydrates thereof, solvatesthereof and polymorphic crystals thereof. The compounds can beadministered as pharmaceutical compositions.

Utility and Administration

The compounds described herein are useful in the methods of theinvention and, while not bound by theory, are believed to exert theirdesirable effects in part through their ability to modulate Wnt-βcatenin signaling. The Wnt pathway is involved in tissue development inembryos and tissue maintenance in adults. It controls a specific set ofgenes that that control cell growth, movement and cell survival. Chronicactivation of these genes and aberrant activation of the Wnt pathwayleads to uncontrolled cell growth and survival and can consequentlydrive cancer formation in a range of tissues including colon, skin,liver and ovary.

The Wnt signaling pathways are a group of signal transduction pathwayswhich begin with proteins that pass signals into a cell through cellsurface receptors. Aberrant activation of the Wnt pathway is implicatedin human cancers, particularly those of the gastrointestinal (GI) tract.Inhibition of aberrant Wnt pathway activity in cancer cell lines canblock their growth, presenting the possibility of new therapeutics.

Wnt ligands bind to LRP⅚ and Frizzled co-receptors present on epithelialcrypt cells, leading to β-catenin stabilization and nucleartranslocation where it binds to the nuclear transcription factor TCF4 todrive a gene-expression program that supports stem cell maintenance,proliferation and differentiation. Activation of Wnt/β-catenin signalingis also crucial for crypt regeneration following injury. Studies havedemonstrated that Respondin 1 (RSPO1), an ISC growth factor and LGR5receptor agonist, activates Wnt/β catenin pathway to repair andregenerate the intestine following chemo-radiation-induced injury. DKK1,a negative regulator Wnt/β-catenin pathway, impairs the RSPO1-inducedintestinal regeneration.

In the absence of a Wnt signal, the transcriptional activator β-cateninis actively degraded in the cell. Phosphorylated β-catenin issubsequently recognized and ubiquitinylated, resulting in itsproteasomal degradation. Levels of free β-catenin consequently remainlow, which allows the DNA-binding T-cell factor/lymphoid enhancer factor(Tcf/Lef) proteins to interact with transcriptional co-repressors toblock target gene expression in the nucleus.

In addition to treating cancer, therapies that control Wnt/β-cateninsignaling also potential in treating other ailments, including fibrosis,inflammatory conditions, bone growth, wound healing, osteoporosis,alopecia (i.e. hair loss), depression and viral infection. Accordingly,there is a need for compounds and methods that can inhibit and/ormodulate Wnt/β-catenin signaling.

BCN057 and Analogs—Cancer Treatment and Therapies

Studies have demonstrated that the Wnt pathway is permanently activatedin both inherited familial adenomatous polyposis and spontaneous formsof colon cancer. Chronic activation of the Wnt pathway in these cellsdrives their expansion into benign adenomas (also termed polyps), whichfrequently progress to invasive colon carcinoma. Approximately 90% ofsporadic colon cancers show aberrant Wnt signaling activity, usually asthe result of mutations in APC.

BCN057 is an anti-neoplastic small molecular that is effective intreating cancer, particularly pancreatic and gastrointestinal (GI)cancers. It can function with dual actions. It induces apoptosis incancer cells. Second, it can promote growth and survival of epithelialcells. BCN057 is particularly effective against pancreatic andgastrointestinal (GI) cancers. BCN057 has demonstrated antineoplasticeffects against “KRAS” cancers.

Use in Conjunction with Radio/Chemo Therapies

BCN057 is effective in treating cancer, particularly pancreatic andgastrointestinal (GI) cancers. In one aspect, disclosed herein, is amethod of treating radiation induced gastrointestinal syndrome (RIGS) ina subject in need thereof, the method comprising the step ofadministering to the subject a therapeutically effective amount of acompound of BCN057 or an analog of BCN057. The analog can be one or moreof the compounds of Formula II-XIX. BCN057 can mitigate RIGS and improvethe therapeutic ratio for abdominal radiotherapy. Further, BCN057mitigates radiation induced mucositis, including oral mucositis, GImucositis, e.g., of the throat, stomach and intestines, enteritis andproctitis. Further, it can prevent and treat damage to epithelial tissuefrom radiation and chemotherapy. The compounds are also useful fortreating or preventing these radiation syndromes associated withradiation therapy.

Combination Therapies

Combination therapy can be particularly effective with drugs that workby different mechanisms, thereby decreasing the likelihood thatresistant cancer cells will develop. When drugs with different effectsare combined, each drug can be used at its optimal dose, withoutintolerable side effects. BCN057 and a second medicament can be combinedfor therapeutic benefit. The second medicant can have a differentmechanism. Alternatively, it can use the same mechanism as BCN057 fortherapeutic benefit. The combination can act via a synergistic effect.Combination therapies can also include additional (e.g. a third, fourth,fifth, etc.) medicaments. BCN512 can be used in combination therapies inthe same manner.

BCN512 and Analogs—SFRP Mediated Therapies

Many colon cancers carry silenced genes encoding members of the secretedFzd-related protein (SFRP) or Wnt inhibitory factor (WIF) families,which act as natural brakes of the Wnt pathway. They can bind with Wntligands to block pathway activation at the cell surface. Without thisinhibition, Wnt ligands produced by the cancer cells can activate thepathway at the membrane and amplify the aberrant Wnt signaling activityinitiated by mutations in APC, β-catenin or Axin 2. This aberrant Wntpathway activation can lead to cancer.

Wnt signaling begins when a Wnt protein binds to the N-terminalextra-cellular cysteine-rich domain of a Frizzled (Fzd) family receptor.When sfrp's are inhibited or at low levels, wnt ligand is able to bindto Fzd receptors and transduce wnt related gene expression. sfrp's alsohave anti-proliferative effects on vascular cells, in vitro and in vivo.In vascular cell cycle, they delay the G1 phase and entry into the Sphase. In kidney development, sFRPS inhibit tubule formation and budgrowth in metanephroi.

BCN512 can inhibit SFRP activity and disrupt its ability to bind wntligands. SFRPs act as negative regulators of wnt signaling by bindingwnt ligand with a similar domain as the fzd receptor domain which wntbinds to when free to transduce canonical wnt signaling. This mechanismpresents several therapeutic uses. BCN512 and its analogs can inhibittissue fibrosis via inhibition SFRP's, including SRFP1. BCN512 and itsanalogs can activate bone growth through inhibition of SRFP's. BCN512and its analogs can activate hair growth through inhibition of SRFP's.

If BCN512 and related structures inhibit the activity of SRFPs, BCN512can allow more free Wnt ligand from epithelial cells. Free Wnt ligandsare secreted and transported through exosomes. To determine the role ofBCN512 in pulmonary epithelium derived Wnt release, exosomes werepurified from organoid conditioned medium. Purified exosomes were testedfor Wnt activity by the TOPFLASH assay. It was observed that exosomalWnt activity is several folds higher in samples prepared from irradiatedorganoids treated with BCN512 compared to irradiated control. Theseresults suggest that BCN512 also induces the endogenous Wnt release.

Additional studies have demonstrated that Wnt β-catenin signaling playsa critical role in restitution of broncho-epithelial stem cell pool. Aprevious study demonstrated that Wnt ligands were secreted andtransported through exosome. It has been demonstrated that exosomederived from mice ex-vivo lung organoids contained Wnt ligands anddemonstrated Wnt activity in response to BCN512 treated. Wnt activityhas also been examined in exosomes derived from human lung organoids.

For the role of BCN512 in human pulmonary epithelium derived Wntrelease, exosome were purified from organoid conditioned medium.Purified exosomes were tested for Wnt activity by TOPFLASH assay. It wasobserved that exosomal Wnt activity is several folds high in samplesprepared from irradiated organoids (4-6 Gy) treated with BCN512 comparedto irradiated control. These results suggest that BCN512 also inducesthe endogenous Wnt release from human pulmonary epithelium.

Inflammatory Diseases

BCN512 can be used to treat inflammatory diseases or conditions.

Inflammatory skin diseases include, conditions associated with cellproliferation, such as psoriasis, eczema and dermatitis, (e.g.,eczematous dermatitides, topic and seborrheic dermatitis, allergic orirritant contact dermatitis, eczema craquelee, photoallergic dermatitis,phototoxic dermatitis, phytophotodermatitis, radiation dermatitis, andstasis dermatitis). Other inflammatory skin diseases include, but arenot limited to, scleroderma, ulcers and erosions resulting from trauma,burns, bullous disorders, or ischemia of the skin or mucous membranes,several forms of ichthyoses, epidermolysis bullosae, hypertrophic scars,keloids, cutaneous changes of intrinsic aging, photoaging, frictionalblistering caused by mechanical shearing of the skin and cutaneousatrophy resulting from the topical use of corticosteroids. Additionalinflammatory skin conditions include inflammation of mucous membranes,such as cheilitis, chapped lips, nasal irritation, mucositis andvulvovaginitis.

Inflammatory disorders of the endocrine system include, but are notlimited to, autoimmune thyroiditis (Hashimoto's disease), Type Idiabetes, and acute and chronic inflammation of the adrenal cortex.Inflammatory conditions of the cardiovascular system include, but arenot limited to, coronary infarct damage, peripheral vascular disease,myocarditis, vasculitis, revascularization of stenosis,artherosclerosis, and vascular disease associated with Type II diabetes.

Inflammatory condition of the kidney include glomerulonephritis,interstitial nephritis, lupus nephritis, nephritis secondary toWegener's disease, acute renal failure secondary to acute nephritis,Goodpasture's syndrome, post-obstructive syndrome, tubular ischemia,irritable bowel disorder, or inflammation induced colon malignancies.

Inflammatory conditions of the liver include hepatitis (arising fromviral infection, autoimmune responses, drug treatments, toxins,environmental agents, or as a secondary consequence of a primarydisorder), biliary atresia, primary biliary cirrhosis and primarysclerosing cholangitis.

Inflammatory conditions of the central nervous system include multiplesclerosis and neurodegenerative diseases such as Alzheimer's disease,Parkinson's disease, or dementia associated with HIV infection.

Other inflammatory conditions include periodontal disease, tissuenecrosis in chronic inflammation, endotoxin shock, smooth muscleproliferation disorders, graft versus host disease, tissue damagefollowing ischemia reperfusion injury, idiopathic pulmonary fibrosis,and tissue rejection following transplant surgery

Treatment of Viral Infections

Additional embodiments include the use of BCN057 and analogs of BCN057for treatment of viral infections. A viral disease infection occurs whenthe body is invaded by pathogenic viruses, and infectious virusparticles attach to and enter susceptible cells. The host immuneresponse can mediate disease and excessive inflammation. The stimulationof the innate and adaptive immune system in response to viral infectionsdestroys infected cells, which can lead to severe pathologicalconsequences to the host (i.e. virus-induced immunopathology).Specifically, immunopathology is caused by the excessive release ofantibodies, interferons and pro-inflammatory cytokines, activation ofthe complement system, or hyperactivity of cytotoxic T cells. Secretionof interferons and other cytokines can trigger cell damage, fever andflu-like symptoms. In severe cases of certain viral infections, as inavian H5N1 influenza in 2005, aberrant induction of the host immuneresponse can elicit a flaring release of cytokines known as a cytokinestorm.

Wnt signaling is important for the innate immune response to viruses.Pathogenic viruses suppress b-catenin downstream expression of criticalgenes to evade the first line of defense in the immune system. b-cateninis essential to the expression of IFN-α/β and the subsequenttranscriptional activation of interferon-stimulated genes. IFN-β inducesin an auto- and paracrine expression of antiviral-acting genes. ThusBCN057 and analogs of BCN057 can prevent pathological consequences suchas virus-induced immunopathology.

Treatment of Depression

Additional embodiments include the use of BCN057 and analogs of BCN057for treatment of depression. Wnt signaling is also important fortreating depression. Since the 1950s Lithium carbonate and other saltshave been used similarly to treat depression. Lithium works byinhibiting GSK3b in the wnt downstream signaling pathway andtranscribing the b-catenin downstream genes.

Recent studies have demonstrated that altered Wnt signalling can play arole in the pathophysiology of mood disorders. β-catenin levels arereduced in the hippocampal CA3 and CA4 regions, and Wnt1 levels areincreased in the hippocampal CA4 region of post-mortem schizophrenicbrains. Because lithium inhibits glycogen synthase kinase3β (GSK3β), acomponent of the canonical Wnt pathway, the pathway has been proposed asa specific target in the treatment of bipolar disorders. Thus, BCN057and analogs of BCN057 can be used to treat depression and mooddisorders.

EXAMPLES

The following non-limiting examples are provided for illustrativepurposes only in order to facilitate a more complete understanding ofrepresentative embodiments now contemplated. These examples should notbe construed to limit any of the embodiments described in the presentspecification, including those pertaining to the compounds,pharmaceutical compositions, or methods and uses disclosed herein.

BCN057 for Treatment of Pancreatic Cancer

FIG. 1 depicts the Effects of 5-FU and BCN057 on the viability ofpancreatic cancer cell lines. The Effects of 5-FU and BCN057 on theviability of pancreatic cancer cell lines were assessed by ATP Liteassay (Perkin Elmer). 50 uM 5Fu (5Fu, n=5), 50 uM 5Fu and 2, 5, 10, and20 uM BCN057 (5Fu+BCN057, n=5) or 2, 5, 10.20 uM CN057 (CN057, n=5).Control cells (V, n=5) The Percent Phosphorylation was calculated bydividing the average value for each condition by the average value ofthe control cells (V) at each time point.

FIGS. 2A and 2B depict the Annexin V Apoptosis and Necrosis Assay inPanc-1 cells. Panc-1 cells were exposed to serial dilutions of 057 inthe presence or absence of the RealTime-Glo™ Annexin V Apoptosis andNecrosis Assay Reagent. The plate was incubated at 37° C./5% CO₂ andluminescence (Annexin V binding) was measured over a period of 6 hours.No change was observed in fluorescence over the same time period.Apoptosis appeared to increase with increasing concentrations of BCN057.FIG. 2A shows apoptosis as observed at 10 minutes (dose dependent). FIG.2B shows apoptosis observed at 10 minutes, 30 minutes, 1 hour and 6hours.

FIG. 3 depicts the Effects of 10 uM BCN057 on the viability ofpancreatic cancer cell lines. The images show pancreatic cancer celllines at time 0 (FIG. 3A), 15 minutes (FIG. 3B), 30 minutes (FIG. 3C),60 minutes (FIG. 3D), 120 minutes (FIG. 3E) and 240 minutes (FIG. 3F).Morphological changes and apoptosis are particularly apparent at 240minutes.

FIGS. 4A and 4B show Compound H, Compound K and the results of aViability Assay on Pancreatic Cells. The graph (FIG. 4A) shows theeffects on viability of Panc-1 cancer cells in the presence of 10 uM ofBCN057, compound H or K over 24, 48 and 72 hours. Each replicate (n=3)is displayed as a ratio of its vehicle control (a % of control). Thenumeric data is also included (FIG. 4B). FIG. 5A depicts Compound H andFIG. 5B depicts Compound K.

The results demonstrate that BCN057 has potent antineoplastic activityand inhibits the proliferation of the tumor cell line. This activity iscomplementary to chemotherapy such as 5-fluoro uracil.

The tests also demonstrate that BCN057 restores apoptosis in pancreaticcancer cells. Conversely, BCN057 allows for survival of stem cells andtherefore prevents damage from chemotherapy induced damage to theepithelial tissue lining alimentary canal and digestive tract.

BCN512 for Treatment of Fibrosis

Fibrosis is generally defined as a pathological wound healing in whichconnective tissue replaces normal parenchymal tissue to the extent thatit goes unchecked, leading to considerable tissue remodelling and theformation of permanent scar tissue. Pulmonary fibrosis is a lung diseasethat occurs when lung tissue becomes damaged and scarred. As explainedin the specification (par. 095), every organ of the body can mount arepair response that generally results in a fibrotic lesion. Lungfibrosis as a result of chronic obstructive pulmonary disease and liverfibrosis because of hepatitis infection are two examples.

We propose that alveolar type II cells function as progenitor cells thatrepair the injured alveolar epithelium. Moreover, damaged epithelialcells also become major source of inflammatory cytokines. Therefore,mitigation of injury and progenitor/stem related re-building of theepithelium is critical to preventing or treating fibrosis

FIG. 6 shows the number of fibrotic lesions in lung sections (untreatedand treated with BCN512). There was a significant reduction in lungfibrosis in the BCN512 treated (20×512) vs. vehicle (20×V) upon finalnecropsy and histological analysis of lung in C57BL mice. Lesions weredefined by local density with five mice per group assessed at day 180.This effect is observed with non-radiation induced stimuli such as LPSand cytotoxic drugs.

Transforming growth factor β (TGF-β) is a central mediator offibrogenesis. TGF-β is upregulated and activated in fibrotic diseasesand modulates fibroblast phenotype and function, inducing myofibroblasttransdifferentiation while promoting matrix preservation. FIG. 7 showsthe histopathology of lung sections stained for TGFβ in C57M Male micereceiving nothing (A), 14Gy thoracic radiation (B) or radiation andBCNB512 (C) and assessed on day 90 respectively. TGFβ is reduced whentreated for the first 20 days post radiation with BCN512 at 5 mg/kg.Images D-F are cardiac muscle stains under the identical parametersabove from the same animals. We noted significant reduction in stainingfor TGFβ. This shows TGFβ staining is lower in tissues from radiationdamage when treated with the BCN512. We expect the same results usingnon-radiation induced stimuli including LPS and cytotoxic drugs.

These studies and observations are consistent with previousobservations, specifically that WNT-catenin signaling promotes theself-renewal and differentiation of LGR5+ epithelial (lung, oral,intestinal) stem cells. Canonical WNT activity was measured in HEK293cells having a TCF/LEF luciferase reporter construct. Luciferaseactivity was measured after 24 hours. BCN-512 treatment significantlyincreased luciferase activity in HEK293 cells compared with vehicletreated cells.

Modulation of macrophage function is also modulated. The absence of lateeffects in fibrosis from animals from long term radiation (observingfrom long term studies of the total body irradiation studies) along withthe reduction of fibroblasts indicate these drugs are effective atpreventing fibrosis and inflammation from both radiation or chemicalmeans (LPS). Moreover, fibroblast proliferation is macrophage dependentand BCN512 inhibits this macrophage function. Together, the resultsdescribed above demonstrate that the compound BCN512 can be administeredto preserve stem cells and progenitor cells. This prevents connectivetissue from replacing normal parenchymal tissue, thus preventingfibrosis.

Pharmaceutical Carriers and Administration

The present methods may prevent a disease or condition or one or moresymptoms of a disease or condition. As used herein, a therapeutic that“prevents” a disorder or condition refers to a compound that, in astatistical sample, reduces the occurrence of the disorder or conditionin the treated sample relative to an untreated control sample, or delaysthe onset or reduces the severity of one or more symptoms of thedisorder or condition relative to the untreated control sample.

The compositions and methods of the present disclosure may be utilizedto treat an individual in need thereof. In certain embodiments, theindividual is a mammal such as a human, or a non-human mammal. Whenadministered to an animal, such as a human, the composition or thecompound is preferably administered or used as a pharmaceuticalcomposition comprising, for example, a compound of the disclosure and apharmaceutically acceptable carrier.

Pharmaceutically acceptable carriers are well known in the art andinclude, for example, aqueous solutions such as water or physiologicallybuffered saline or other solvents or vehicles such as glycols, glycerol,oils such as olive oil, or injectable organic esters. In a preferredembodiment, when such pharmaceutical compositions are for humanadministration, particularly for invasive routes of administration(i.e., routes, such as injection or implantation, that circumventtransport or diffusion through an epithelial barrier), the aqueoussolution is pyrogen-free, or substantially pyrogen-free. The excipientscan be chosen, for example, to effect delayed release of an agent or toselectively target one or more cells, tissues or organs. Thepharmaceutical composition can be in dosage unit form such as tablet,capsule (including sprinkle capsule and gelatin capsule), granule,lyophilized for reconstitution, powder, solution, syrup, suppository,injection or the like. The composition can also be present in atransdermal delivery system, e.g., a skin patch.

A pharmaceutical composition disclosed herein may comprise a therapeuticcompound in an amount sufficient to allow customary administration to anindividual. In certain embodiments, a pharmaceutical compositiondisclosed herein may comprise, e.g., at least 5 mg, at least 10 mg, atleast 15 mg, at least 20 mg, at least 25 mg, at least 30 mg, at least 35mg, at least 40 mg, at least 45 mg, at least 50 mg, at least 55 mg, atleast 60 mg, at least 65 mg, at least 70 mg, at least 75 mg, at least 80mg, at least 85 mg, at least 90 mg, at least 95 mg, or at least 100 mgof a therapeutic compound. In certain embodiments, a pharmaceuticalcomposition disclosed herein may comprise, e.g., at least 5 mg, at least10 mg, at least 20 mg, at least 25 mg, at least 50 mg, at least 75 mg,at least 100 mg, at least 200 mg, at least 300 mg, at least 400 mg, atleast 500 mg, at least 600 mg, at least 700 mg, at least 800 mg, atleast 900 mg, at least 1,000 mg, at least 1,100 mg, at least 1,200 mg,at least 1,300 mg, at least 1,400 mg, or at least 1,500 mg of atherapeutic compound. In yet other aspects of this embodiment, apharmaceutical composition disclosed herein may comprise in the rangeof, e.g., about 5 mg to about 100 mg, about 10 mg to about 100 mg, about50 mg to about 150 mg, about 100 mg to about 250 mg, about 150 mg toabout 350 mg, about 250 mg to about 500 mg, about 350 mg to about 600mg, about 500 mg to about 750 mg, about 600 mg to about 900 mg, about750 mg to about 1,000 mg, about 850 mg to about 1,200 mg, or about 1,000mg to about 1,500 mg. In still certain embodiments, a pharmaceuticalcomposition disclosed herein may comprise in the range of, e.g., about10 mg to about 250 mg, about 10 mg to about 500 mg, about 10 mg to about750 mg, about 10 mg to about 1,000 mg, about 10 mg to about 1,500 mg,about 50 mg to about 250 mg, about 50 mg to about 500 mg, about 50 mg toabout 750 mg, about 50 mg to about 1,000 mg, about 50 mg to about 1,500mg, about 100 mg to about 250 mg, about 100 mg to about 500 mg, about100 mg to about 750 mg, about 100 mg to about 1,000 mg, about 100 mg toabout 1,500 mg, about 200 mg to about 500 mg, about 200 mg to about 750mg, about 200 mg to about 1,000 mg, about 200 mg to about 1,500 mg,about 5 mg to about 1,500 mg, about 5 mg to about 1,000 mg, or about 5mg to about 250 mg.

A pharmaceutical composition disclosed herein may comprise a solvent,emulsion or other diluent in an amount sufficient to dissolve atherapeutic compound disclosed herein. In certain embodiments, apharmaceutical composition disclosed herein may comprise a solvent,emulsion or a diluent in an amount of, e.g., less than about 90% (v/v),less than about 80% (v/v), less than about 70% (v/v), less than about65% (v/v), less than about 60% (v/v), less than about 55% (v/v), lessthan about 50% (v/v), less than about 45% (v/v), less than about 40%(v/v), less than about 35% (v/v), less than about 30% (v/v), less thanabout 25% (v/v), less than about 20% (v/v), less than about 15% (v/v),less than about 10% (v/v), less than about 5% (v/v), or less than about1% (v/v). In certain embodiments, a pharmaceutical composition disclosedherein may comprise a solvent, emulsion or other diluent in an amount ina range of, e.g., about 1% (v/v) to 90% (v/v), about 1% (v/v) to 70%(v/v), about 1% (v/v) to 60% (v/v), about 1% (v/v) to 50% (v/v), about1% (v/v) to 40% (v/v), about 1% (v/v) to 30% (v/v), about 1% (v/v) to20% (v/v), about 1% (v/v) to 10% (v/v), about 2% (v/v) to 50% (v/v),about 2% (v/v) to 40% (v/v), about 2% (v/v) to 30% (v/v), about 2% (v/v)to 20% (v/v), about 2% (v/v) to 10% (v/v), about 4% (v/v) to 50% (v/v),about 4% (v/v) to 40% (v/v), about 4% (v/v) to 30% (v/v), about 4% (v/v)to 20% (v/v), about 4% (v/v) to 10% (v/v), about 6% (v/v) to 50% (v/v),about 6% (v/v) to 40% (v/v), about 6% (v/v) to 30% (v/v), about 6% (v/v)to 20% (v/v), about 6% (v/v) to 10% (v/v), about 8% (v/v) to 50% (v/v),about 8% (v/v) to 40% (v/v), about 8% (v/v) to 30% (v/v), about 8% (v/v)to 20% (v/v), about 8% (v/v) to 15% (v/v), or about 8% (v/v) to 12%(v/v).

The final concentration of a therapeutic compound disclosed herein in apharmaceutical composition disclosed herein may be of any suitableconcentration. In certain embodiments, the final concentration of atherapeutic compound in a pharmaceutical composition may be atherapeutically effective amount. In certain embodiments, the finalconcentration of a therapeutic compound in a pharmaceutical compositionmay be, e.g., at least 0.00001 mg/mL, at least 0.0001 mg/mL, at least0.001 mg/mL, at least 0.01 mg/mL, at least 0.1 mg/mL, at least 1 mg/mL,at least 10 mg/mL, at least 25 mg/mL, at least 50 mg/mL, at least 100mg/mL, at least 200 mg/mL, at least 500 mg/mL, at least 700 mg/mL, atleast 1,000 mg/mL, or at least 1,200 mg/mL. In certain embodiments, theconcentration of a therapeutic compound disclosed herein in the solutionmay be, e.g., at most 1,000 mg/mL, at most 1,100 mg/mL, at most 1,200mg/mL, at most 1,300 mg/mL, at most 1,400 mg/mL, at most 1,500 mg/mL, atmost 2,000 mg/mL, at most 2,000 mg/mL, or at most 3,000 mg/mL. Incertain embodiments, the final concentration of a therapeutic compoundin a pharmaceutical composition may be in a range of, e.g., about0.00001 mg/mL to about 3,000 mg/mL, about 0.0001 mg/mL to about 3,000mg/mL, about 0.01 mg/mL to about 3,000 mg/mL, about 0.1 mg/mL to about3,000 mg/mL, about 1 mg/mL to about 3,000 mg/mL, about 250 mg/mL toabout 3,000 mg/mL, about 500 mg/mL to about 3,000 mg/mL, about 750 mg/mLto about 3,000 mg/mL, about 1,000 mg/mL to about 3,000 mg/mL, about 100mg/mL to about 2,000 mg/mL, about 250 mg/mL to about 2,000 mg/mL, about500 mg/mL to about 2,000 mg/mL, about 750 mg/mL to about 2,000 mg/mL,about 1,000 mg/mL to about 2,000 mg/mL, about 100 mg/mL to about 1,500mg/mL, about 250 mg/mL to about 1,500 mg/mL, about 500 mg/mL to about1,500 mg/mL, about 750 mg/mL to about 1,500 mg/mL, about 1,000 mg/mL toabout 1,500 mg/mL, about 100 mg/mL to about 1,200 mg/mL, about 250 mg/mLto about 1,200 mg/mL, about 500 mg/mL to about 1,200 mg/mL, about 750mg/mL to about 1,200 mg/mL, about 1,000 mg/mL to about 1,200 mg/mL,about 100 mg/mL to about 1,000 mg/mL, about 250 mg/mL to about 1,000mg/mL, about 500 mg/mL to about 1,000 mg/mL, about 750 mg/mL to about1,000 mg/mL, about 100 mg/mL to about 750 mg/mL, about 250 mg/mL toabout 750 mg/mL, about 500 mg/mL to about 750 mg/mL, about 100 mg/mL toabout 500 mg/mL, about 250 mg/mL to about 500 mg/mL, about 0.00001 mg/mLto about 0.0001 mg/mL, about 0.00001 mg/mL to about 0.001 mg/mL, about0.00001 mg/mL to about 0.01 mg/mL, about 0.00001 mg/mL to about 0.1mg/mL, about 0.00001 mg/mL to about 1 mg/mL, about 0.001 mg/mL to about0.01 mg/mL, about 0.001 mg/mL to about 0.1 mg/mL, about 0.001 mg/mL toabout 1 mg/mL, about 0.001 mg/mL to about 10 mg/mL, or about 0.001 mg/mLto about 100 mg/mL.

In certain embodiments, a therapeutically effective amount of atherapeutic compound disclosed herein generally is in the range of about0.001 mg/kg/day to about 100 mg/kg/day. In certain embodiments, aneffective amount of a therapeutic compound disclosed herein may be,e.g., at least 0.001 mg/kg/day, at least 0.01 mg/kg/day, at least 0.1mg/kg/day, at least 1.0 mg/kg/day, at least 5.0 mg/kg/day, at least 10mg/kg/day, at least 15 mg/kg/day, at least 20 mg/kg/day, at least 25mg/kg/day, at least 30 mg/kg/day, at least 35 mg/kg/day, at least 40mg/kg/day, at least 45 mg/kg/day, or at least 50 mg/kg/day. In certainembodiments, an effective amount of a therapeutic compound disclosedherein may be in the range of, e.g., about 0.001 mg/kg/day to about 10mg/kg/day, about 0.001 mg/kg/day to about 15 mg/kg/day, about 0.001mg/kg/day to about 20 mg/kg/day, about 0.001 mg/kg/day to about 25mg/kg/day, about 0.001 mg/kg/day to about 30 mg/kg/day, about 0.001mg/kg/day to about 35 mg/kg/day, about 0.001 mg/kg/day to about 40mg/kg/day, about 0.001 mg/kg/day to about 45 mg/kg/day, about 0.001mg/kg/day to about 50 mg/kg/day, about 0.001 mg/kg/day to about 75mg/kg/day, about 0.001 mg/kg/day to about 100 mg/kg/day, about 0.001mg/kg/day to about 150 mg/kg/day, about 0.001 mg/kg/day to about 200mg/kg/day, about 0.001 mg/kg/day to about 250 mg/kg/day, about 0.001mg/kg/day to about 300 mg/kg/day, about 0.001 mg/kg/day to about 350mg/kg/day, about 0.001 mg/kg/day to about 400 mg/kg/day, about 0.001mg/kg/day to about 450 mg/kg/day, about 0.001 mg/kg/day to about 500mg/kg/day, about 0.001 mg/kg/day to about 550 mg/kg/day, about 0.001mg/kg/day to about 600 mg/kg/day, about 0.001 mg/kg/day to about 650mg/kg/day, about 0.001 mg/kg/day to about 700 mg/kg/day, about 0.001mg/kg/day to about 750 mg/kg/day, or about 0.001 mg/kg/day to about 800mg/kg/day. In yet other aspects of this embodiment, an effective amountof a therapeutic compound disclosed herein may be in the range of, e.g.,about 0.01 mg/kg/day to about 10 mg/kg/day, about 0.01 mg/kg/day toabout 15 mg/kg/day, about 0.01 mg/kg/day to about 20 mg/kg/day, about0.01 mg/kg/day to about 25 mg/kg/day, about 0.01 mg/kg/day to about 30mg/kg/day, about 0.01 mg/kg/day to about 35 mg/kg/day, about 0.01mg/kg/day to about 40 mg/kg/day, about 0.01 mg/kg/day to about 45mg/kg/day, about 0.01 mg/kg/day to about 50 mg/kg/day, about 0.01mg/kg/day to about 75 mg/kg/day, about 0.01 mg/kg/day to about 100mg/kg/day, about 0.01 mg/kg/day to about 150 mg/kg/day, about 0.01mg/kg/day to about 200 mg/kg/day, about 0.01 mg/kg/day to about 250mg/kg/day, about 0.01 mg/kg/day to about 300 mg/kg/day, about 0.01mg/kg/day to about 350 mg/kg/day, about 0.01 mg/kg/day to about 400mg/kg/day, about 0.01 mg/kg/day to about 450 mg/kg/day, about 0.01mg/kg/day to about 500 mg/kg/day, about 0.01 mg/kg/day to about 550mg/kg/day, about 0.01 mg/kg/day to about 600 mg/kg/day, about 0.01mg/kg/day to about 650 mg/kg/day, about 0.01 mg/kg/day to about 700mg/kg/day, about 0.01 mg/kg/day to about 750 mg/kg/day, or about 0.01mg/kg/day to about 800 mg/kg/day. In certain embodiments, an effectiveamount of a therapeutic compound disclosed herein may be in the rangeof, e.g., about 0.1 mg/kg/day to about 10 mg/kg/day, about 0.1 mg/kg/dayto about 15 mg/kg/day, about 0.1 mg/kg/day to about 20 mg/kg/day, about0.1 mg/kg/day to about 25 mg/kg/day, about 0.1 mg/kg/day to about 30mg/kg/day, about 0.1 mg/kg/day to about 35 mg/kg/day, about 0.1mg/kg/day to about 40 mg/kg/day, about 0.1 mg/kg/day to about 45mg/kg/day, about 0.1 mg/kg/day to about 50 mg/kg/day, about 0.1mg/kg/day to about 75 mg/kg/day, about 0.1 mg/kg/day to about 100mg/kg/day, about 0.1 mg/kg/day to about 150 mg/kg/day, about 0.1mg/kg/day to about 200 mg/kg/day, about 0.1 mg/kg/day to about 250mg/kg/day, about 0.1 mg/kg/day to about 300 mg/kg/day, about 0.1mg/kg/day to about 350 mg/kg/day, about 0.1 mg/kg/day to about 400mg/kg/day, about 0.1 mg/kg/day to about 450 mg/kg/day, about 0.1mg/kg/day to about 500 mg/kg/day, about 0.1 mg/kg/day to about 550mg/kg/day, about 0.1 mg/kg/day to about 600 mg/kg/day, about 0.1mg/kg/day to about 650 mg/kg/day, about 0.1 mg/kg/day to about 700mg/kg/day, about 0.1 mg/kg/day to about 750 mg/kg/day, or about 0.1mg/kg/day to about 800 mg/kg/day. In certain embodiments, an effectiveamount of a therapeutic compound disclosed herein may be in the rangeof, e.g., about 10 mg/kg/day to about 15 mg/kg/day, about 10 mg/kg/dayto about 20 mg/kg/day, about 10 mg/kg/day to about 25 mg/kg/day, about10 mg/kg/day to about 30 mg/kg/day, about 10 mg/kg/day to about 35mg/kg/day, about 10 mg/kg/day to about 40 mg/kg/day, about 10 mg/kg/dayto about 45 mg/kg/day, about 10 mg/kg/day to about 50 mg/kg/day, about10 mg/kg/day to about 75 mg/kg/day, about 10 mg/kg/day to about 100mg/kg/day, about 10 mg/kg/day to about 150 mg/kg/day, about 10 mg/kg/dayto about 200 mg/kg/day, about 10 mg/kg/day to about 250 mg/kg/day, about10 mg/kg/day to about 300 mg/kg/day, about 10 mg/kg/day to about 350mg/kg/day, about 10 mg/kg/day to about 400 mg/kg/day, about 10 mg/kg/dayto about 450 mg/kg/day, about 10 mg/kg/day to about 500 mg/kg/day, about10 mg/kg/day to about 550 mg/kg/day, about 10 mg/kg/day to about 600mg/kg/day, about 10 mg/kg/day to about 650 mg/kg/day, about 10 mg/kg/dayto about 700 mg/kg/day, about 10 mg/kg/day to about 750 mg/kg/day, orabout 10 mg/kg/day to about 800 mg/kg/day.

In other aspects of this embodiment, an effective amount of atherapeutic compound disclosed herein may be in the range of, e.g.,about 1 mg/kg/day to about 10 mg/kg/day, about 1 mg/kg/day to about 15mg/kg/day, about 1 mg/kg/day to about 20 mg/kg/day, about 1 mg/kg/day toabout 25 mg/kg/day, about 1 mg/kg/day to about 30 mg/kg/day, about 1mg/kg/day to about 35 mg/kg/day, about 1 mg/kg/day to about 40mg/kg/day, about 1 mg/kg/day to about 45 mg/kg/day, about 1 mg/kg/day toabout 50 mg/kg/day, about 1 mg/kg/day to about 75 mg/kg/day, or about 1mg/kg/day to about 100 mg/kg/day. In certain embodiments, an effectiveamount of a therapeutic compound disclosed herein may be in the rangeof, e.g., about 5 mg/kg/day to about 10 mg/kg/day, about 5 mg/kg/day toabout 15 mg/kg/day, about 5 mg/kg/day to about 20 mg/kg/day, about 5mg/kg/day to about 25 mg/kg/day, about 5 mg/kg/day to about 30mg/kg/day, about 5 mg/kg/day to about 35 mg/kg/day, about 5 mg/kg/day toabout 40 mg/kg/day, about 5 mg/kg/day to about 45 mg/kg/day, about 5mg/kg/day to about 50 mg/kg/day, about 5 mg/kg/day to about 75mg/kg/day, or about 5 mg/kg/day to about 100 mg/kg/day.

In liquid and semi-solid formulations, a concentration of a therapeuticcompound disclosed herein typically may be between about 50 mg/mL toabout 1,000 mg/mL. In certain embodiments, a therapeutically effectiveamount of a therapeutic disclosed herein may be from, e.g., about 50mg/mL to about 100 mg/mL, about 50 mg/mL to about 200 mg/mL, about 50mg/mL to about 300 mg/mL, about 50 mg/mL to about 400 mg/mL, about 50mg/mL to about 500 mg/mL, about 50 mg/mL to about 600 mg/mL, about 50mg/mL to about 700 mg/mL, about 50 mg/mL to about 800 mg/mL, about 50mg/mL to about 900 mg/mL, about 50 mg/mL to about 1,000 mg/mL, about 100mg/mL to about 200 mg/mL, about 100 mg/mL to about 300 mg/mL, about 100mg/mL to about 400 mg/mL, about 100 mg/mL to about 500 mg/mL, about 100mg/mL to about 600 mg/mL, about 100 mg/mL to about 700 mg/mL, about 100mg/mL to about 800 mg/mL, about 100 mg/mL to about 900 mg/mL, about 100mg/mL to about 1,000 mg/mL, about 200 mg/mL to about 300 mg/mL, about200 mg/mL to about 400 mg/mL, about 200 mg/mL to about 500 mg/mL, about200 mg/mL to about 600 mg/mL, about 200 mg/mL to about 700 mg/mL, about200 mg/mL to about 800 mg/mL, about 200 mg/mL to about 900 mg/mL, about200 mg/mL to about 1,000 mg/mL, about 300 mg/mL to about 400 mg/mL,about 300 mg/mL to about 500 mg/mL, about 300 mg/mL to about 600 mg/mL,about 300 mg/mL to about 700 mg/mL, about 300 mg/mL to about 800 mg/mL,about 300 mg/mL to about 900 mg/mL, about 300 mg/mL to about 1,000mg/mL, about 400 mg/mL to about 500 mg/mL, about 400 mg/mL to about 600mg/mL, about 400 mg/mL to about 700 mg/mL, about 400 mg/mL to about 800mg/mL, about 400 mg/mL to about 900 mg/mL, about 400 mg/mL to about1,000 mg/mL, about 500 mg/mL to about 600 mg/mL, about 500 mg/mL toabout 700 mg/mL, about 500 mg/mL to about 800 mg/mL, about 500 mg/mL toabout 900 mg/mL, about 500 mg/mL to about 1,000 mg/mL, about 600 mg/mLto about 700 mg/mL, about 600 mg/mL to about 800 mg/mL, about 600 mg/mLto about 900 mg/mL, or about 600 mg/mL to about 1,000 mg/mL.

The subject may be a human, rat, mouse, cat, dog, horse, sheep, cow,monkey, avian, or amphibian. In another embodiment, the cell is in vivoor in vitro. Typical subjects to which compounds of the disclosure maybe administered will be mammals, particularly primates, especiallyhumans. For veterinary applications, a wide variety of subjects will besuitable, e.g. livestock such as cattle, sheep, goats, cows, swine andthe like; poultry such as chickens, ducks, geese, turkeys, and the like;and domesticated animals particularly pets such as dogs and cats. Fordiagnostic or research applications, a wide variety of mammals will besuitable subjects including rodents (e.g. mice, rats, hamsters),rabbits, primates, and swine such as inbred pigs and the like.Additionally, for in vitro applications, such as in vitro diagnostic andresearch applications, body fluids and cell samples of the abovesubjects will be suitable for use such as mammalian, particularlyprimate such as human, blood, urine or tissue samples, or blood urine ortissue samples of the animals mentioned for veterinary applications.

When administering to an organism, the compound may be administered byany suitable means. In some embodiments, the compounds or formulationsare administered orally. In some embodiments, the compounds orformulations are administered by injection, e.g. subcutaneous,parenteral, or intravenous, injections.

In some embodiments the compound may be administered in combination withother potential mitigators. In a particular embodiment, the compositionmay be administered with growth factors, NSAIDs, chemotherapeutics,anti-inflammatories, antibiotics, Metformin (Glucophage, Glumetza,others), Sulfonylureas, Meglitinides, Thiazolidinediones, DPP-4inhibitors, GLP-1 receptor agonists, SGLT2 inhibitors, and/or Insulintherapy, for the treatment of the above conditions. In one aspect, thegrowth factor can be G-CSF (aka filgrastim, NEUPOGEN®) or erythropoietin(aka EPOGEN®).

In other embodiments, the compositions may comprise an effective amountof a modulator and/or other pharmaceutically active agent in aphysiologically-acceptable carrier. The carrier may take a wide varietyof forms depending on the form of preparation desired for a particularroute of administration. Suitable carriers and their formulation aredescribed, for example, in Remington's Pharmaceutical Sciences by E. W.Martin. In some embodiments, the compound may be contained in anyappropriate amount in any suitable carrier substance, and is generallypresent in an amount of 1-95% by weight of the total weight of thecomposition. The composition may be provided in a dosage form that issuitable for parenteral (e.g., subcutaneously, intravenously,intramuscularly, or intraperitoneally) or oral administration route. Thepharmaceutical compositions may be formulated according to conventionalpharmaceutical practice (see, e.g., Remington: The Science and Practiceof Pharmacy (20th ed.), ed. A. R. Gennaro, Lippincott Williams &Wilkins, 2000 and Encyclopedia of Pharmaceutical Technology, eds. J.Swarbrick and J. C. Boylan, 1988-1999, Marcel Dekker, New York).

In some embodiments, the compositions may be in a form suitable foradministration by sterile injection. In one example, to prepare such acomposition, the compositions(s) are dissolved or suspended in aparenterally acceptable liquid vehicle. Among acceptable vehicles andsolvents that may be employed are water, water adjusted to a suitable pHby addition of an appropriate amount of hydrochloric acid, sodiumhydroxide or a suitable buffer, 1,3-butanediol, Ringer's solution, andisotonic sodium chloride solution and dextrose solution. The aqueousformulation may also contain one or more preservatives (e.g., methyl,ethyl or n-propyl p-hydroxybenzoate). For parenteral formulations, thecarrier will usually comprise sterile water, though other ingredients,for example, ingredients that aid solubility or for preservation, may beincluded. Injectable solutions may also be prepared in which caseappropriate stabilizing agents may be employed. In one embodiment, theformulation includes at least one or more of methanesulfonic acid,povidone, benzyl alcohol, n-Methyl pyrrolidone, ethanol, Poloxamer 188,lactic acid, Captisol (SBE-beta-CD), or Vitamin E, such as TPGS (d-alphatocopheryl polyethylene glycol 1000 succinate).

Formulations suitable for parenteral administration usually comprise asterile aqueous preparation of the compound, which may be isotonic withthe blood of the recipient (e.g., physiological saline solution). Suchformulations may include suspending agents and thickening agents andliposomes or other microparticulate systems which are designed to targetthe compound to blood components or one or more organs. The formulationsmay be presented in unit-dose or multi-dose form.

Parenteral administration may comprise any suitable form of systemicdelivery or localized delivery. Administration may for example beintravenous, intra-arterial, intrathecal, intramuscular, subcutaneous,intramuscular, intra-abdominal (e.g., intraperitoneal), etc., and may beeffected by infusion pumps (external or implantable) or any othersuitable means appropriate to the desired administration modality.

In some embodiments, the compositions may be in a form suitable for oraladministration. In compositions in oral dosage form, any of the usualpharmaceutical media may be employed. Thus, for liquid oralpreparations, such as, for example, suspensions, elixirs and solutions,suitable carriers and additives include water, glycols, oils, alcohols,flavoring agents, preservatives, coloring agents and the like. For solidoral preparations such as, for example, powders, capsules and tablets,suitable carriers and additives include starches, sugars, diluents,granulating agents, lubricants, binders, disintegrating agents and thelike. If desired, tablets may be sugar coated or enteric coated bystandard techniques.

Compositions suitable for oral administration may be presented asdiscrete units such as capsules, cachets, tablets, or lozenges, eachcontaining a predetermined amount of the active ingredient as a powderor granules. Optionally, a suspension in an aqueous liquor or anon-aqueous liquid may be employed, such as a syrup, an elixir, anemulsion, or a draught. Formulations for oral use include tabletscontaining active ingredient(s) in a mixture with pharmaceuticallyacceptable excipients. Such formulations are known to the skilledartisan. Excipients may be, for example, inert diluents or fillers(e.g., sucrose, sorbitol, sugar, mannitol, microcrystalline cellulose,starches including potato starch, calcium carbonate, sodium chloride,lactose, calcium phosphate, calcium sulfate, or sodium phosphate);granulating and disintegrating agents (e.g., cellulose derivativesincluding microcrystalline cellulose, starches including potato starch,croscarmellose sodium, alginates, or alginic acid); binding agents(e.g., sucrose, glucose, sorbitol, acacia, alginic acid, sodiumalginate, gelatin, starch, pregelatinized starch, microcrystallinecellulose, magnesium aluminum silicate, carboxymethylcellulose sodium,methylcellulose, hydroxypropyl methylcellulose, ethylcellulose,polyvinylpyrrolidone, or polyethylene glycol); and lubricating agents,glidants, and antiadhesives (e.g., magnesium stearate, zinc stearate,stearic acid, silicas, hydrogenated vegetable oils, or talc). Otherpharmaceutically acceptable excipients can be colorants, flavoringagents, plasticizers, humectants, buffering agents, and the like.

A syrup can be made by adding the compound to a concentrated aqueoussolution of a sugar, for example sucrose, to which may also be added anyaccessory ingredient(s). Such accessory ingredient(s) may includeflavorings, suitable preservative, agents to retard crystallization ofthe sugar, and agents to increase the solubility of any otheringredient, such as a polyhydroxy alcohol, for example glycerol orsorbitol.

In some embodiments, the composition can be in a form of nasal or othermucosal spray formulations (e.g. inhalable forms). These formulationscan include purified aqueous solutions of the active compounds withpreservative agents and isotonic agents. Such formulations can beadjusted to a pH and isotonic state compatible with the nasal or othermucous membranes. Alternatively, they can be in the form of finelydivided solid powders suspended in a gas carrier. Such formulations maybe delivered by any suitable means or method, e.g., by nebulizer,atomizer, metered dose inhaler, or the like.

In some embodiments, the composition may be in a form suitable forrectal administration. These formulations may be presented as asuppository with a suitable carrier such as cocoa butter, hydrogenatedfats, or hydrogenated fatty carboxylic acids.

In some embodiments, the composition may be in a form suitable fortransdermal administration. These formulations may be prepared, forexample, by incorporating the active compound in a thixotropic orgelatinous carrier such as a cellulosic medium, e.g., methyl celluloseor hydroxyethyl cellulose, with the resulting formulation then beingpacked in a transdermal device adapted to be secured in dermal contactwith the skin of a wearer.

In addition to the aforementioned ingredients, compositions of thedisclosure may further include one or more accessory ingredient(s)selected from encapsulants, diluents, buffers, flavoring agents,binders, disintegrants, surface active agents, thickeners, lubricants,preservatives (including antioxidants), and the like.

In some embodiments, compositions may be formulated for immediaterelease, sustained release, delayed-onset release or any other releaseprofile known to one skilled in the art. In some embodiments, thepharmaceutical composition may be formulated to release the activecompound substantially immediately upon administration or at anypredetermined time or time period after administration. The latter typesof compositions are generally known as controlled release formulations,which include (i) formulations that create a substantially constantconcentration of the drug within the body over an extended period oftime; (ii) formulations that after a predetermined lag time create asubstantially constant concentration of the drug within the body over anextended period of time; (iii) formulations that sustain action during apredetermined time period by maintaining a relatively constant,effective level in the body with concomitant minimization of undesirableside effects associated with fluctuations in the plasma level of theactive substance (sawtooth kinetic pattern); (iv) formulations thatlocalize action by, e.g., spatial placement of a controlled releasecomposition adjacent to or in the central nervous system orcerebrospinal fluid; (v) formulations that allow for convenient dosing,such that doses are administered, for example, once every one or twoweeks; and (vi) formulations that target the site of a pathology. Forsome applications, controlled release formulations obviate the need forfrequent dosing to sustain activity at a medically advantageous level.

Any of a number of strategies can be pursued in order to obtaincontrolled release in which the rate of release outweighs the rate ofmetabolism of the compound in question. In one example, controlledrelease is obtained by appropriate selection of various formulationparameters and ingredients, including, e.g., various types of controlledrelease compositions and coatings. Thus, the compound is formulated withappropriate excipients into a pharmaceutical composition that, uponadministration, releases the compound in a controlled manner. Examplesinclude single or multiple unit tablet or capsule compositions, oilsolutions, suspensions, emulsions, microcapsules, microspheres,molecular complexes, nanoparticles, patches, and liposomes.

In some embodiments, the composition may comprise a “vectorized” form,such as by encapsulation of the compound in a liposome or otherencapsulate medium, or by fixation of the compound, e.g., by covalentbonding, chelation, or associative coordination, on a suitablebiomolecule, such as those selected from proteins, lipoproteins,glycoproteins, and polysaccharides.

In some embodiments, the composition can be incorporated intomicrospheres, microcapsules, nanoparticles, liposomes, or the like forcontrolled release. Furthermore, the composition may include suspending,solubilizing, stabilizing, pH-adjusting agents, tonicity adjustingagents, and/or dispersing, agents. Alternatively, the compound may beincorporated in biocompatible carriers, implants, or infusion devices.

Materials for use in the preparation of microspheres and/ormicrocapsules are, e.g., biodegradable/bioerodible polymers such aspolyglactin, poly-(isobutyl cyanoacrylate),poly(2-hydroxyethyl-L-glutamine) and, poly(lactic acid). Biocompatiblecarriers that may be used when formulating a controlled releaseparenteral formulation are carbohydrates (e.g., dextrans), proteins(e.g., albumin), lipoproteins, or antibodies. Materials for use inimplants can be non-biodegradable (e.g., polydimethyl siloxane) orbiodegradable (e.g., poly(caprolactone), poly(lactic acid),poly(glycolic acid) or poly(ortho esters) or combinations thereof).

In all embodiments, the compound or other active compounds may bepresent as pharmaceutically acceptable salts or other derivatives, suchas ether derivatives, ester derivatives, acid derivatives, and aqueoussolubility altering derivatives of the active compound. Derivativesinclude all individual enantiomers, diastereomers, racemates, and otherisomers of the compounds. Derivatives also include all polymorphs andsolvates, such as hydrates and those formed with organic solvents, ofthe compounds. Such isomers, polymorphs, and solvates may be prepared bymethods known in the art, such as by regiospecific and/orenantioselective synthesis and resolution.

The ability to prepare salts depends on the acidity or basicity of thecompounds. Suitable salts of the compounds include, but are not limitedto, acid addition salts, such as those made with hydrochloric,hydrobromic, hydroiodic, perchloric, sulfuric, nitric, phosphoric,acetic, propionic, glycolic, lactic pyruvic, malonic, succinic, maleic,fumaric, malic, tartaric, citric, benzoic, carbonic, cinnamic, mandelic,methanesulfonic, ethanesulfonic, hydroxyethanesulfonic, benzenesulfonic,p-toluene sulfonic, cyclohexanesulfamic, salicyclic, p-aminosalicylic,2-phenoxybenzoic, and 2-acetoxybenzoic acid; salts made with saccharin;alkali metal salts, such as sodium and potassium salts; alkaline earthmetal salts, such as calcium and magnesium salts; and salts formed withorganic or inorganic ligands, such as quaternary ammonium salts.

Additional suitable salts include, but are not limited to, acetate,benzenesulfonate, benzoate, bicarbonate, bisulfate, bitartrate, borate,bromide, calcium edetate, camsylate, carbonate, chloride, clavulanate,citrate, dihydrochloride, edetate, edisylate, estolate, esylate,fumarate, gluceptate, gluconate, glutamate, glycollylarsanilate,hexylresorcinate, hydrabamine, hydrobromide, hydrochloride,hydroxynaphthoate, iodide, isothionate, lactate, lactobionate, laurate,malate, maleate, mandelate, mesylate, methylbromide, methylnitrate,methylsulfate, mucate, napsylate, nitrate, N-methylglucamine ammoniumsalt, oleate, pamoate (embonate), palmitate, pantothenate,phosphate/diphosphate, polygalacturonate, salicylate, stearate, sulfate,subacetate, succinate, tannate, tartrate, teoclate, tosylate,triethiodide and valerate salts of the compounds.

The pharmaceutically acceptable acid addition salts can also exist asvarious solvates, such as with water, methanol, ethanol,dimethylformamide, and the like. Mixtures of such solvates can also beprepared. The source of such solvate can be from the solvent ofcrystallization, inherent in the solvent of preparation orcrystallization, or adventitious to such solvent.

Wetting agents, emulsifiers and lubricants, such as sodium laurylsulfate and magnesium stearate, as well as coloring agents, releaseagents, coating agents, sweetening, flavoring and perfuming agents,preservatives and antioxidants can also be present in the compositions.

Examples of pharmaceutically acceptable antioxidants include: (1)water-soluble antioxidants, such as ascorbic acid, cysteinehydrochloride, sodium bisulfate, sodium metabisulfite, sodium sulfiteand the like; (2) oil-soluble antioxidants, such as ascorbyl palmitate,butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT),lecithin, propyl gallate, alpha-tocopherol, and the like; and (3)metal-chelating agents, such as citric acid, ethylenediamine tetraaceticacid (EDTA), sorbitol, tartaric acid, phosphoric acid, and the like.

Unless the context clearly indicates otherwise, compositions of allembodiments can comprise various pharmaceutically acceptable salts, orother derivatives described above.

The formulation and preparation of such compositions are well known tothose skilled in the art of pharmaceutical formulation. Formulations canbe found in Remington: The Science and Practice of Pharmacy.

The amount of the compound employed in the present disclosure to be usedvaries according to the condition, the patient/subject, and the extentof the condition.

The contents of all cited references (including literature references,issued patents, published patent applications) as cited throughout thisapplication are hereby expressly incorporated by reference. Thedisclosure and the manner and process of making and using it, aredescribed in such full, clear, concise and exact terms as to enable anyperson skilled in the art to which it pertains, to make and use thesame.

Actual dosage levels of the active ingredients in the pharmaceuticalcompositions may be varied so as to obtain an amount of the activeingredient that is effective to achieve the desired therapeutic responsefor a particular patient, composition, and mode of administration,without being toxic to the patient.

The selected dosage level will depend upon a variety of factorsincluding the activity of the particular compound or combination ofcompounds employed, or the ester, salt or amide thereof, the route ofadministration, the time of administration, the rate of excretion of theparticular compound(s) being employed, the duration of the treatment,other drugs, compounds and/or materials used in combination with theparticular compound(s) employed, the age, sex, weight, condition,general health and prior medical history of the patient being treated,and like factors well known in the medical arts.

A physician or veterinarian having ordinary skill in the art can readilydetermine and prescribe the therapeutically effective amount of thepharmaceutical composition required. For example, the physician orveterinarian could start doses of the pharmaceutical composition orcompound at levels lower than that required in order to achieve thedesired therapeutic effect and gradually increase the dosage until thedesired effect is achieved. By “therapeutically effective amount” ismeant the concentration of a compound that is sufficient to elicit thedesired therapeutic effect. It is generally understood that theeffective amount of the compound will vary according to the weight, sex,age, and medical history of the subject. Other factors which influencethe effective amount may include, but are not limited to, the severityof the patient's condition, the disorder being treated, the stability ofthe compound, and, if desired, another type of therapeutic agent beingadministered with the compound of the disclosure. A larger total dosecan be delivered by multiple administrations of the agent.

Methods to determine efficacy and dosage are known to those skilled inthe art (Isselbacher et al. (1996) Harrison's Principles of InternalMedicine 13 ed., 1814-1882, herein incorporated by reference).

In general, a suitable daily dose of an active compound used in thecompositions and methods of the disclosure will be that amount of thecompound that is the lowest dose effective to produce a therapeuticeffect. Such an effective dose will generally depend upon the factorsdescribed above.

Dosing can be single dosage or cumulative (serial dosing), and can bereadily determined by one skilled in the art. For instance, treatmentmay comprise a one-time administration of an effective dose of apharmaceutical composition disclosed herein. Alternatively, treatmentmay comprise multiple administrations of an effective dose of apharmaceutical composition carried out over a range of time periods,such as, e.g., once daily, twice daily, thrice daily, once every fewdays, or once weekly. The timing of administration can vary fromindividual to individual, depending upon such factors as the severity ofan individual's symptoms. For example, an effective dose of apharmaceutical composition disclosed herein can be administered to anindividual once daily for an indefinite period of time, or until theindividual no longer requires therapy. A person of ordinary skill in theart will recognize that the condition of the individual can be monitoredthroughout the course of treatment and that the effective amount of apharmaceutical composition disclosed herein that is administered can beadjusted accordingly.

If desired, the effective daily dose of the active compound may beadministered as one, two, three, four, five, six or more sub-dosesadministered separately at appropriate intervals throughout the day,optionally, in unit dosage forms. In certain embodiments of the presentdisclosure, the active compound may be administered two or three timesdaily. In preferred embodiments, the active compound will beadministered once daily.

In certain embodiments, the period of administration of a therapeuticcompound is for 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8days, 9 days, 10 days, 11 days, 12 days, 13 days, 14 days, 3 weeks, 4weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks,12 weeks, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10months, 11 months, 12 months, or more. In certain embodiments, atreatment regimen may comprise a period during which administration isstopped for 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8days, 9 days, 10 days, 11 days, 12 days, 13 days, 14 days, 3 weeks, 4weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks,12 weeks, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10months, 11 months, 12 months, or more.

The patient receiving this treatment is any animal in need, includingprimates, in particular humans, and other mammals such as equines,cattle, swine and sheep, and poultry and pets in general.

In other embodiments, the compounds described herein may be providedwith the one or more additional therapeutic agents in a kit, e.g., asseparate pharmaceutical formulations capable of being used together in aconjoint therapy as discussed herein, either together in a singlecontainer or in separate containers. In certain such embodiments, thekit may further include instructions for the conjoint administration ofthe pharmaceutical formulations, e.g., for treating or preventing any ofthe conditions discussed above.

Such combination products may employ compounds of this disclosure, orpharmaceutically acceptable salts thereof, within the dosage rangedescribed hereinbefore and the other pharmaceutically-active agentwithin its approved dosage range.

In some embodiments, the compound may be administered after thepredicate event, such as after exposure to ionizing radiation, or afterthe initiation of exposure to radiation including accidental ortherapeutic radiation. In one embodiment, the compound is administeredimmediately after the exposure. In another embodiment, the compound isadministered within 12 hours of the exposure. In another embodiment, thecompound is administered within 24 hours of the exposure. In anotherembodiment, the compound is administered at 24 hours after the exposure.In another embodiment, the compound is administered after 24 hours ofexposure. In another embodiment, the compound is administered after 36hours of exposure. In another embodiment, the compound is administeredwithin 48 hours of exposure. In another embodiment, the compound isadministered within 60 hours of exposure. In another embodiment, thecompound is administered within 72 hours of the exposure. In anotherembodiment, the compound is administered within 84 hours of theexposure.

In a certain embodiment or a particular formulation Yel002/BCN057 wassolubalized in aqueous solution at physiologically compatible pHs using100 mM methanesulfonic acid (MSA)/10% povidone (PVP); 100 mM MSA/2%benzyl alcohol/2% N-methylpyrrolidone (NMP); and, 100 mM MSA/10%ethanol/1% Poloxamer 188. In a further aspect 100 mM lactic acid wasadded and also improved solubility for these mixtures. In yet anotherembodiment, a formulation comprising Yel002 and 30 wt % Captisol(SBE-beta-CD) and 100 mM MSA yielded excellent solubility at up to pH4.1 or higher.

In another embodiment formulation for intravenous, subcutaneous and oraldelivery of therapeutic levels of Yel002/BCN057 were developedcomprising 30 wt % Captisol (SBE-beta-CD) and 100 mM MSA at pH 4.1 orhigher (adjusted with 1.0 N NaOH).

The disclosure now being generally described, it will be more readilyunderstood by reference to the following examples which are includedmerely for purposes of illustration of certain aspects and embodimentsof the present disclosure and are not intended to limit the disclosure.

In other aspects of this embodiment, a molecule disclosed herein reducesthe severity of a disease by, e.g., at least 10%, at least 15%, at least20%, at least 25%, at least 30%, at least 35%, at least 40%, at least45%, at least 50%, at least 55%, at least 60%, at least 65%, at least70%, at least 75%, at least 80%, at least 85%, at least 90% or at least95%. In yet other aspects of this embodiment, a fusion protein orchimeric molecule disclosed herein reduces the severity of a diseasefrom, e.g., about 5% to about 100%, about 10% to about 100%, about 20%to about 100%, about 30% to about 100%, about 40% to about 100%, about50% to about 100%, about 60% to about 100%, about 70% to about 100%,about 80% to about 100%, about 10% to about 90% about 20% to about 90%,about 30% to about 90%, about 40% to about 90%, about 50% to about 90%,about 60% to about 90%, about 70% to about 90%, about 10% to about 80%,about 20% to about 80%, about 30% to about 80%, about 40% to about 80%,about 50% to about 80%, or about 60% to about 80%, about 10% to about70%, about 20% to about 70%, about 30% to about 70%, about 40% to about70%, or about 50% to about 70%.

In closing, it is to be understood that although aspects of the presentspecification are highlighted by referring to specific embodiments, oneskilled in the art will readily appreciate that these disclosedembodiments are only illustrative of the principles of the subjectmatter disclosed herein. Therefore, it should be understood that thedisclosed subject matter is in no way limited to a particular compound,composition, article, apparatus, methodology, protocol, and/or reagent,etc., described herein, unless expressly stated as such. In addition,those of ordinary skill in the art will recognize that certain changes,modifications, permutations, alterations, additions, subtractions andsub-combinations thereof can be made in accordance with the teachingsherein without departing from the spirit of the present specification.It is therefore intended that the following appended claims and claimshereafter introduced are interpreted to include all such changes,modifications, permutations, alterations, additions, subtractions andsub-combinations as are within their true spirit and scope.

Certain embodiments of the present disclosure are described herein,including the best mode known to the inventors for carrying out thedisclosure. Of course, variations on these described embodiments willbecome apparent to those of ordinary skill in the art upon reading theforegoing description. The inventor expects skilled artisans to employsuch variations as appropriate, and the inventors intend for the presentdisclosure to be practiced otherwise than specifically described herein.Accordingly, this disclosure includes all modifications and equivalentsof the subject matter recited in the claims appended hereto as permittedby applicable law. Moreover, any combination of the above-describedembodiments in all possible variations thereof is encompassed by thedisclosure unless otherwise indicated herein or otherwise clearlycontradicted by context.

Groupings of alternative embodiments, elements, or steps of the presentdisclosure are not to be construed as limitations. Each group member maybe referred to and claimed individually or in any combination with othergroup members disclosed herein. It is anticipated that one or moremembers of a group may be included in, or deleted from, a group forreasons of convenience and/or patentability. When any such inclusion ordeletion occurs, the specification is deemed to contain the group asmodified thus fulfilling the written description of all Markush groupsused in the appended claims.

All patents, patent publications, and other publications referenced andidentified in the present specification are individually and expresslyincorporated herein by reference in their entirety for the purpose ofdescribing and disclosing, for example, the compositions andmethodologies described in such publications that might be used inconnection with the present disclosure. These publications are providedsolely for their disclosure prior to the filing date of the presentapplication. Nothing in this regard should be construed as an admissionthat the inventors are not entitled to antedate such disclosure byvirtue of prior disclosure or for any other reason. All statements as tothe date or representation as to the contents of these documents isbased on the information available to the applicants and does notconstitute any admission as to the correctness of the dates or contentsof these documents.

Lastly, the terminology used herein is for the purpose of describingparticular embodiments only, and is not intended to limit the scope ofthe present disclosure, which is defined solely by the claims.Accordingly, the present disclosure is not limited to that precisely asshown and described.

What is claimed is:
 1. A compound of Formula C or an analog thereof,

wherein the analog is selected from Formula XXI, Formula XXII, FormulaXXIII, Formula XXIV, Formula XXV, Formula XXVI and Formula XXVII:


2. A method of treating inflammation in a subject, the method comprisingadministering to the subject a therapeutically effective amount of thecompound of claim
 1. 3. A method of modulating Wnt activity to treat anailment in a subject, the method comprising administering to the subjecta therapeutically effective amount of a compound of the compound ofclaim
 1. 4. The method of claim 3, wherein the ailment is at least ofradiation exposure, fibrosis, insulin sensitivity, cancer, osteoporosis,alopecia/hair growth, wound healing, low bone density and obesity. 5.The method of claim 4, wherein the fibrosis is one or more of pulmonaryfibrosis, idiopathic pulmonary fibrosis, acute respiratory distresssyndrome, cystic fibrosis, non-cystic fibrosis bronchiectasis,cirrhosis, liver fibrosis, endomyocardial fibrosis, old myocardialinfarction, atrial fibrosis, mediastinal fibrosis, myelofibrosis,retroperitoneal fibrosis, progressive massive fibrosis, nephrogenicsystemic fibrosis, Crohn's disease, gastrointestinal fibrosis, keloidconditions, scleroderma/systemic sclerosis, arthofibrosis, peyronie'sdisease, dupuytren's contracture, oral submucous fibrosis, liverfibrosis, gastrointestinal fibrosis, renal fibrosis from kidney dialysisor adhesive capsulitis.
 6. A method of modulating Wnt activity to treatan ailment in a subject, comprising administering to the subject atherapeutically effective amount of a compound having the structure ofFormula Ia:

wherein: A⁵ is a secondary or tertiary amino substituent, and A⁶ is asubstituted or unsubstituted aryl or heteroaryl group.
 7. The method ofclaim 6, wherein the ailment is at least of radiation exposure,fibrosis, insulin sensitivity, cancer, osteoporosis, alopecia/hairgrowth, wound healing, low bone density and obesity.
 8. The method ofclaim 6, wherein the ailment is one or more side effects of chemotherapyor radiotherapy.
 9. A method of modulating Wnt activity to treat anailment in a subject, the method comprising administering to the subjecta therapeutically effective amount of a compound of having the structureof Formula IIa:

wherein: Y¹ and Y² taken together with X form:

wherein X is N, C or CH; G is N, C or CH; Z is absent or selected fromsubstituted or unsubstituted alkyl, heteroalkyl, alkenyl, or alkynyl;and R⁴ is absent or selected from substituted or unsubstituted aryl; andR⁵ and R⁶ are each independently absent or lower alkyl.
 10. The methodof claim 9, wherein the ailment is at least one of radiation exposure,fibrosis, insulin sensitivity, cancer, osteoporosis, alopecia/hairgrowth, wound healing, low bone density and obesity.
 11. The method ofclaim 10, wherein the fibrosis is one or more of pulmonary fibrosis,idiopathic pulmonary fibrosis, acute respiratory distress syndrome,cystic fibrosis, non-cystic fibrosis bronchiectasis, cirrhosis, liverfibrosis, endomyocardial fibrosis, old myocardial infarction, atrialfibrosis, mediastinal fibrosis, myelofibrosis, retroperitoneal fibrosis,progressive massive fibrosis, nephrogenic systemic fibrosis, Crohn'sdisease, gastrointestinal fibrosis, keloid conditions,scleroderma/systemic sclerosis, arthofibrosis, peyronie's disease,dupuytren's contracture, oral submucous fibrosis, liver fibrosis,gastrointestinal fibrosis, renal fibrosis from kidney dialysis oradhesive capsulitis.
 13. The method of claim 9, wherein the ailment isone or more side effects of chemotherapy or radiotherapy.